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Published on 18 November 2016 on http://pubs.rsc.org | doi:10.1039/9781782629276-FP001
Allosterism in Drug Discovery

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RSC Drug Discovery Series
Editor-in-chief
Professor David Thurston, King’s College, London, UK
Series Editors:
Professor David Rotella, Montclair State University, USA
Professor Ana Martinez, Centro de Investigaciones Biologicas-CSIC,
Madrid, Spain
Dr David Fox, Vulpine Science and Learning, UK
Advisor to the Board:

Professor Robin Ganellin, University College London, UK
Titles in the Series:

1: Metabolism, Pharmacokinetics and Toxicity of Functional Groups
2: Emerging Drugs and Targets for Alzheimer’s Disease; Volume 1
3: Emerging Drugs and Targets for Alzheimer’s Disease; Volume 2
4: Accounts in Drug Discovery
5: New Frontiers in Chemical Biology
6: Animal Models for Neurodegenerative Disease
7: Neurodegeneration
8: G Protein-Coupled Receptors
9: Pharmaceutical Process Development
10: Extracellular and Intracellular Signaling
11: New Synthetic Technologies in Medicinal Chemistry
12: New Horizons in Predictive Toxicology
13: Drug Design Strategies: Quantitative Approaches
14: Neglected Diseases and Drug Discovery
15: Biomedical Imaging
16: Pharmaceutical Salts and Cocrystals
17: Polyamine Drug Discovery
18: Proteinases as Drug Targets
19: Kinase Drug Discovery
20: Drug Design Strategies: Computational Techniques and Applications
21: Designing Multi-Target Drugs
22: Nanostructured Biomaterials for Overcoming Biological Barriers
23: Physico-Chemical and Computational Approaches to Drug Discovery
24: Biomarkers for Traumatic Brain Injury
25: Drug Discovery from Natural Products
26: Anti-Inflammatory Drug Discovery
27: New Therapeutic Strategies for Type 2 Diabetes: Small Molecules
28: Drug Discovery for Psychiatric Disorders
29: Organic Chemistry of Drug Degradation
30: Computational Approaches to Nuclear Receptors
31: Traditional Chinese Medicine
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32: Successful Strategies for the Discovery of Antiviral Drugs

33: Comprehensive Biomarker Discovery and Validation for Clinical
Application
34: Emerging Drugs and Targets for Parkinson's Disease
35: Pain Therapeutics; Current and Future Treatment Paradigms

36: Biotherapeutics: Recent Developments using Chemical and Molecular
Biology
37: Inhibitors of Molecular Chaperones as Therapeutic Agents
38: Orphan Drugs and Rare Diseases
39: Ion Channel Drug Discovery
40: Macrocycles in Drug Discovery
41: Human-based Systems for Translational Research
42: Venoms to Drugs: Venom as a Source for the Development of Human
Therapeutics
43: Carbohydrates in Drug Design and Discovery
44:Drug Discovery for Schizophrenia
45: Cardiovascular and Metabolic Disease: Scientific Discoveries and New
Therapies
46: Green Chemistry Strategies for Drug Discovery
47: Fragment-Based Drug Discovery
48: Epigenetics for Drug Discovery
49: New Horizons in Predictive Drug Metabolism and Pharmacokinetics
50: Privileged Scaffolds in Medicinal Chemistry: Design, Synthesis, Evaluation
51: Nanomedicines: Design, Delivery and Detection
52: Synthetic Methods in Drug Discovery: Volume 1
53: Synthetic Methods in Drug Discovery: Volume 2
54: Drug Transporters: Role and Importance in ADME and Drug Development
55: Drug Transporters: Recent Advances and Emerging Technologies
56: Allosterism in Drug Discovery
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Edited by
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Alcyoneus/ScienceWorks, Sparta, New Jersey, USA
Email: [email protected]
Published on 18 November 2016 on http://pubs.rsc.org | doi:10.1039/9781782629276-FP001 View Online
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Preface
I went to sleep one evening, very tired after a long, cold winter day in the hills
of northwestern New Jersey. I felt like I could sleep for a thousand years… and
then, like thunder, the thought struck my mind: if I did just that and woke up
in the 30th century, what would drug discovery be like? How would it have
changed? What diseases would still be incurable, and which ones will not
exist anymore? And how would our current efforts be seen, in retrospect? I
took the precaution of making a note of that idea, so that I would not forget
(as it has happened in the past) and I could work on it the next morning.
Drug discovery is an interesting human endeavor in that nobody knows
exactly how to succeed. We try different strategies hoping that the next
time we will get it right. We swung from the purported, process-centered
“industrialization” of the late 1990's to the explosion of innovation of the
2010's. When I began my pharmaceutical research career we worked in
ultra-secretive laboratories in buildings without windows to preclude any-
one walking outside from getting the slightest idea of what we were doing
indoors. In contrast, openness is now flourishing and precompetitive collab-
orations are a necessity today, as alliances are forming at a high pace to inte-
grate emerging knowledge generated in academia into industrial new drug
projects. This interdependence among different sectors in the “Life Science
Ecosystem” is key to the future of drug discovery.
As a testament to that spirit, this book is co-authored by scientists from
academia and industry, roughly in equal proportion. And we, the co-authors,
come from many different scientific fields, such as molecular pharmacology,
cell biology, medicinal chemistry, computational chemistry, and chemical
biology. Working together we are trying to make the future come faster. This
spirit of collaboration should not be taken for granted, and I sincerely hope it
is nurtured and developed for the next thousand years by future generations
of scientists.

Edited by Dario Doller
Published by the Royal Society of Chemistry, www.rsc.org
vii
View Online
viii Preface
This book aims to be a time capsule documenting the initial stages of apply-
ing allosteric modulation principles to drug discovery. Allosterism has been
known for some 50 years. However, it is relatively recently that we started
trying to incorporate it systematically into our arsenal of drug modalities. As
allosterism is broadly seen in nature, we are presenting examples from the

work of experts in areas such as enzymes, transporters, ion channels, and
G-protein-coupled receptors. I suspect allosterism will become a stepping
stone in our journey to understanding human life at the molecular level.
Diversity of thought is an important component in the creation of new
scientific knowledge. All authors have been challenged to present their most
advanced views in their field of expertise. They were also given complete
freedom to express their perspectives in areas that are constantly expanding.
Every single one of them took the risk, and all deserve credit for doing so.
With that in mind, I hope the reader will gain diverse, and perhaps not
always converging, insight coming from many different perspectives gained
throughout our efforts to understand allosterism. In editing this work, I have
aimed to preserve a feeling that these are our current best approaches to
study allosterism in drug discovery, but knowing that we still have a lot to
learn. Indeed, I personally have greatly broadened my own views on the topic
and learned a lot from editing the input to this book and related scientific
reports.
So, whether you are reading this in 2016 or in 3016, you should know that
we, the co-authors, came together to get to the future as soon as possible.
As long as the time to deliver a new drug treatment is measured in decades,
every difference than we can make along the way could have tremendous
impact on the lives of patients and their families. That is the sacrament of
those working in drug discovery, always.
I am grateful to my fellow co-authors for joining me in this endeavor, which
I hope they found rewarding and worthy of their time and efforts. I thank
Harriet Manning, Rowan Frame, and Antonia Pass, from the Royal Society of
Chemistry, for their guidance. Special thanks to Dr Dave Rotella – an excel-
lent medicinal chemist and colleague – for the opportunity he gave me to
lead this effort and interact together.
Finally, and humbly, I would like to acknowledge five mentors who had
major impact in my professional and personal life over a number of years.
In chronological order, the late Professor Eduardo G. Gros, the late Professor
Derek H. R. Barton, Dr Bill Greenlee, Dr Frank Larsen, and Dr Al Robichaud
supported, challenged, and inspired me. Without them, I would not be where
I am today. Wherever you are, I hope you see a part of yourselves reflected in
this work.
Dario Doller
With admiration, to all drug hunters who pursue Nature's truths

To my wife Cecilia, our daughter Miranda, and our dogs, Willie Nelson, and
Ricky, who make our home my place in the World
Contents
Chapter 1 Modulation of Biological Targets Using
Allosteric Ligands: Food for Thought 1
Dario Doller and Xinyan Huang
1.1 Drug Discovery in the Early 21st Century 1

1.2 Allostery: A 50-Year Old Concept 2
1.3 Allosteric Drugs: The Right Tool at the Right Time 6
1.4 Potential Advantages of Allosteric Modulators Over
Orthosteric Ligands… or are They? 7
1.5 Looking Under the Hood 10
1.6 “Pure” PAMs and Ago-PAMs 14
1.7 Flat SAR 15
1.8 Functional Switches 18
1.9 Concluding Remarks 18
Acknowledgements 19
References 19
Chapter 2 Identifying and Quantifying Allosteric Drug Function 24

Terry Kenakin
2.1 Introduction: Receptor Allosterism 24

2.2 Unique Effects of Allosteric Antagonists 25
2.3 Detecting Allosteric Effect 27
2.3.1 Saturation of Effect 27
2.3.2 Probe Dependence 28
2.4 The Functional Allosteric Receptor Model 28
2.5 Negative Allosteric Modulators (NAMs) 30
2.5.1 Pharmacologic Resultant Analysis 32
2.5.2 PAM-Antagonists 34

xi
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xii Contents
2.6 Kinetics 36
2.7 Conclusions 37
References 37
Chapter 3 Targeting Catalytic and Non-Catalytic Functions of

Protein Kinases 40
Susanne Müller and Stefan Knapp
3.1 Introduction 40
3.2 The Kinase Active State 42
3.3 Inactive States: An Opportunity for Selective
Targeting? 46
3.4 Highly Selective Kinase Inhibitors Target Unique
Binding Pockets 47
3.5 Allosteric Inhibitors 49
3.6 Examples: Back Pocket Binders Recognizing a
Stable DFG-In Conformation 51
3.7 Examples: Back Pocket Binders Recognizing a
Stable DFG-Out Conformation 51
3.8 Differential Effects of Type I and Type II
Inhibitors in Signalling 54
3.9 Pseudokinases as Drug Targets? 56
3.10 Conclusions 57
References 58
Chapter 4 Molecular Biology Techniques Applied to GPCR Allosteric

and Biased Ligands 65
Mélanie Frauli, Christel Franchet, Ismet Dorange,
Arturo Mancini, Billy Breton and Stephan Schann
4.1 Introduction 65
4.2 Primary HTS Assays for Allosteric Modulators of
GPCRs 68
4.2.1 Binding Studies for AM Identification and
Characterization 68
4.2.2 Functional Tests 74
4.3 Complementary Assays for AM
Characterization 84
4.3.1 GTP Gamma S 84
4.3.2 Label-Free Assays 84
4.4 GPCR Biased Ligands: Concepts and Promises 86
4.4.1 Multiparametric Profiling with BRET-Based
Biosensors 87
4.5.1 Combining Technologies to Discover Biased
Allosteric Modulators 88
4.5.2 Further Considerations 89
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Contents xiii
Conflict of Interest 90
Acknowledgements 90
References 90
Chapter 5 Examining Allosterism in a Dimeric G-Protein-Coupled

Receptor Context 97
Jesús Giraldo, Jordi Ortiz, James Dalton and Bin Zhou
5.1 G-Protein-Coupled Receptors: Paradigms of

Allosteric Machines 97
5.2 A Decision to be Made by the Receptor: To
Bind a G Protein or to Bind a β-Arrestin? 99
5.2.1 How GPCRs Recognize G Proteins:
The µ-Opioid Receptor as an Example 99
5.2.2 Dancing with Another Partner:
The β-Arrestin Signalling Pathway 102
5.2.3 This Decision Can be Affected by the
Allosteric Interactions Between Orthosteric
and Allosteric Ligands 104
5.3 The Complexity and Versatility that
Oligomerisation Imparts to GPCR Signalling 104
5.3.1 Metabotropic Glutamate Receptors: Where
Dimerization Meets Allosterism 105
5.4 Getting Help from Mechanistic Mathematical
Models: The mGlu Receptor as an Example 113
5.4.1 Modelling the Transmission of the Signal
Through the ECD 113
5.4.2 Modelling Cooperativity Effects Between
the ECD and the TMD 115
5.5 Concluding Remarks and Future Work 118
Appendix 118
Acknowledgements 124
References 124
Chapter 6 A Unifying Approach to the Duality of “Energetic” Versus

“Conformational” Formulations of Allosteric Coupling:
Mechanistic Implications for GPCR Allostery 131
H. Ongun Onaran and Tommaso Costa
6.1 Introduction 131

6.2 Dualism in the Definitions of Allostery 134
6.3 Structural Changes and Receptor Allostery 140
6.4 Allosteric Coupling as the Result of Probability
Distributions of Receptor States 145
6.5 Conclusions 151
References 151
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xiv Contents
Chapter 7 mGlu2 Receptor Positive Allosteric Modulators 156
A. A. Trabanco, J. M. Cid and G. Tresadern

7.2 mGlu2 Receptor Positive Allosteric Modulators 157

7.2.1 Medicinal Chemistry of mGlu2 Receptor
PAMs 158
7.2.2 mGlu Structure and mGlu2 PAM Binding
Modes 166
7.3 Conclusions 167
References 168
Chapter 8 Muscarinic Receptors Allosteric Modulation 175

Bruce J. Melancon and Corey R. Hopkins

8.2 Recent Advances with M1 and M4 Bitopic Ligands 177
8.3 Recent Advances with M4 Allosteric Ligands 179
8.3.1 Current Efforts Using LY2033298 179
8.3.2 M4 Positive Allosteric Modulators
Developed at Vanderbilt University 180
8.4 Recent Advances in M1 Positive Allosteric
Modulators 183
8.4.1 Quinolinone and Quinolizidinone Scaffolds 183
8.4.2 Tricyclic Positive Allosteric Modulators 185
8.4.3 Indole–Oxindole Scaffolds 186
8.5 Recent Advances in M5 Negative and Positive
Allosteric Modulation 187
8.6 Conclusions 188
References 189
Chapter 9 Positive Allosteric Modulators of Opioid Receptors 194

Kristin L. Rockwell and Andrew Alt
9.1 Opioid Receptors and Pain 194

9.2 Allosteric Modulation 195
9.3 Potential Utility of Opioid Receptor PAMs for Pain
Management 197
9.4 Endogenous Opioid Signaling 199
9.5 Enkephalinase Inhibitors 200
9.6 Discovery and Characterization of µ-Opioid
Receptor PAMs 200
9.7 Structure–Activity Relationship Studies and the
Identification of µ-Opioid Receptor SAMs 208
9.8 Mount Sinai Chemotype 208
9.9 δ-Opioid Receptor Selective PAMs 211
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Contents xv
9.10 Proposed Binding Site for Opioid Receptor PAMs 213
9.11 Discussion and Future Directions 214
References 216
Chapter 10 mGlu4 PET Ligands as Enablers of Target Biology

Understanding 220
Zhaoda Zhang, Pekka Poutiainen and Anna-Liisa Brownell

10.1.1 Metabotropic Glutamate Receptor
4 (mGlu4) 221
10.1.2 mGlu4 and Parkinson’s Disease 221
10.1.3 Positron Emission Tomography (PET)
Imaging 222
10.2 mGlu4 Ligands 224
10.2.1 Orthosteric Agonists and Antagonists 225
10.2.2 Allosteric Modulators 226
10.2.3 Selection of mGlu4 Ligands 228
10.3 Co-Operative Binding Assay 228
10.4 Development of mGlu4 PET Ligands 231
10.4.1 N-(4-Chloro-3-
[11C]methoxyphenyl)picolinamide ([11C]14) 231
10.4.2 N-(3-Chloro-4-(4-[18F]fluoro-1,3-dioxoisoindolin-
2-yl)phenyl)-2-picolinamide ([18F]18) 232
10.4.3 Re-Exploring the N-Phenylpicolinamide
Derivatives 235
10.4.4 N-(3-([11C]Methylthio)phenyl)picolinamide
([11C]26) 237
10.4.5 5-Methyl-N-(4-[11C] methylpyrimidin-2-yl)-4-
(1H-pyrazol-4-yl)thiazol-2-amine ([11C]20) 240
10.5 Functional Modulation of GPCRs During
Parkinson-Disease-Like Neurodegeneration 241
10.6 Conclusions 242
References 243
Chapter 11 Allosteric Modulators of Adenosine, P2Y and P2X

Receptors 247
Kenneth A. Jacobson and Zhan-Guo Gao

11.2 Adenosine Receptor (AR) Allosteric
Modulation 249
11.2.1 Allosteric Modulators of the A1AR 250
11.2.2 Allosteric Modulators of the A2AAR and A2BAR 252
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xvi Contents
11.2.3 Allosteric Modulators of the A3AR 253
11.2.4 Mutagenesis of ARs to Locate Residues
Involved in Interaction with PAMs 255
11.3 P2YR Allosteric Modulation 255
11.3.1 NAMs of the P2Y1R 256

11.3.2 Allosteric Modulation of the P2Y2R 257
11.3.3 Allosteric Modulation of the P2Y4R 257
11.3.4 Modulation of the P2Y12R 257
11.4 P2XR Allosteric Modulation 258
11.4.1 Allosteric Modulation of the P2X2R,
P2X3R, and P2X2/3R 258
11.4.2 Allosteric Modulation of the P2X4R 261
11.4.3 Allosteric Modulation of the P2X7R 261
Abbreviations 262
References 264
Chapter 12 Positive Allosteric Modulators of G-Protein-Coupled

Receptors that Act via Covalent Mechanisms of Action 271
Whitney M. Nolte and Philip A. Carpino

12.2 Pharmacology of Compound 2 and BETP 273
12.3 Mechanistic Studies with BETP and Compound 2 274
12.4 Covalent Mechanism for BETP and Compound 2 275
References 279
Chapter 13 Mechanism of Action of a GluN2C- and GluN2D-Selective

NMDA Receptor Positive Allosteric Modulator 281
Katie L. Strong, Matthew P. Epplin, Yao Jing,
Stephen F. Traynelis and Dennis C. Liotta

13.2 Therapeutic Rationale for NMDA Receptor
Positive Allosteric Modulators 285
13.2.1 Schizophrenia 285
13.2.2 Cognitive Enhancement 286
13.2.3 Anxiety Disorders 287
13.3 Mechanism of Action and Structural Determinants
of CIQ 287
13.3.1 Mechanism of Action 287
13.3.2 Structural Determinants of Activity 290
13.4 Off-Target Testing and the Selectivity of CIQ for the
NMDA Receptor 293
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Contents xvii
13.5 Pharmacokinetics of CIQ 293
13.6 Utility of CIQ as a Pharmacological Probe 294
13.6.1 CIQ as a Pharmacological Probe for Fear
Acquisition and Fear Extinction 294
13.6.2 CIQ as a Pharmacological Probe for

Schizophrenia 295
13.6.3 CIQ as a Pharmacological Probe to Study
Parkinson’s Disease 297
13.7 Overview of SAR for the Tetrahydroisoquinoline
Class of Compounds Selective for the GluN2C- and
GluN2D-Containing NMDA Receptors 299
References 301
Chapter 14 Development of AMPA Receptor Modulators as

Cognition Enhancers 310
Craig Jamieson and Emma L. Duffy

14.2 Structure and Function of the AMPA Receptors 311
14.3 Chemical Classes of AMPA Receptor Positive
Allosteric Modulators 314
14.4 Impact of Biostructural Data 325
14.5 Summary and Outlook 328
References 329
Chapter 15 Allosteric Modulation of Neuronal Nicotinic

Acetylcholine Receptors 334
Mark M. Levandoski and Sivaramakrishna Koganti

15.2 Nicotinic Receptors Display Broad Expression and
Function 335
15.3 Nicotinic Receptors are Built for Diversity 338
15.4 Explaining Nicotinic Receptor Pharmacology
Requires Allostery 340
15.5 Nicotinic Receptors Offer Diverse Therapeutic
Targets 342
15.6 How Can Ligand Site Identification Elucidate
Allosteric Mechanisms? 344
15.6.1 Transmembrane Domain Sites 345
15.6.2 Extracellular Inter-Subunit Cleft Sites 347
15.7 Total Synthesis 351
References 353
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xviii Contents
Chapter 16 Allosteric Binding in the Serotonin Transporter –
Pharmacology, Structure, Function and Potential
Use as a Novel Drug Target 360
Claus J. Loland, Connie Sanchez, Per Plenge, Klaus P. Bøgesø
and Benny Bang-Andersen

16.2 The Allosteric Binding Site in SERT 364
16.2.1 Early Findings of Allosteric Properties
with SERT Ligands 364
16.2.2 Location of the Allosteric Binding Site in
SERT 365
16.2.3 Is Allosteric SERT Modulation
Therapeutically Relevant? 369
16.3 Ligands that Bind to the S2 Site on SERT 371
16.4 Conclusions and Perspective 377
References 378
Chapter 17 Allosteric Inhibition of Abl Kinase 381

Anna Lucia Fallacara, Silvia Schenone and Maurizio Botta

17.2 Structure of Abl Kinase 382
17.3 Intramolecular Interactions Regulating Abl Activity 385
17.3.1 The Complex Mechanism of Abl Inactivation 385
17.3.2 Mechanisms of Abl Activation 386
17.4 The Importance of Abl in Cancer Development 387
17.4.1 Bcr–Abl Kinase 387
17.4.2 The T315I Mutant 388
17.5 Bcr–Abl Allosteric Modulation: From ATP Pocket
Binders to Allosteric Inhibitors 389
17.5.1 Myristate Pocket Binders: Abl Inhibitors 390
17.5.2 Myristate Pocket Binders: Abl Activators 398
References 400
Chapter 18 Allosteric Modulators of Heat Shock Protein 90 (HSP90) 404

Yen Chin Koay and Shelli McAlpine
18.1 Introduction: Molecular Chaperones 404

18.2 Heat Shock Protein 90 405
18.3 HSP90 Function 408
18.4 HSP90 Inhibitors 409
18.4.1 HSP90 Inhibitors that Target the
N-Terminus 411
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Contents xix
18.4.2 C-Terminal Binders 415
18.4.3 C-Terminal Modulators 416
References 421
Subject Index 427

Published on 18 November 2016 on http://pubs.rsc.org | doi:10.1039/9781782629276-00001
Chapter 1
Modulation of Biological
Targets Using Allosteric
Ligands: Food for Thought
Dario Doller*a and Xinyan Huangb
a
Alcyoneus/ScienceWorks, Sparta, NJ 07871, USA; bOffice of Therapeutics
Alliances, New York University Langone Medical Center, One Park Avenue,
6th Floor, New York, NY 10016, USA
*E-mail: [email protected]
1.1 Drug Discovery in the Early 21st Century

The dawn of the new century found several major pharmaceutical companies
facing significant challenges in keeping their pipelines populated with new
drugs. For nearly two decades, robust increases in research and development
investments had not produced the hoped for number of new medical enti-
ties (NMEs) approvals per year. In some therapeutic areas such as diseases of
the central nervous system (CNS), and in spite of a growing patient popula-
tion and major medical needs, only a handful of new drugs were approved
during this period, and mostly based on mechanisms already known (“me
too” drugs). As a response to this crisis of innovation, and propelled by major
discoveries in molecular and cell biology research, in particular in the areas
of oncology and immunology, a chemically broad range of new therapeutic
modalities emerged, such as antibodies, proteins, nucleic acids, vaccines,

1
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2 Chapter 1
cell, or gene therapies. These are generally grouped under the denomination
“biologics”, to differentiate them from “small molecules”. Drugs in the latter
group have historically been mostly thought of as acting competitively with
endogenous ligands, binding at their target receptors in a model that became
known as “lock and key”.1 These two types of drugs differ in terms of a num-
ber of attributes, such as molecular weight, preparation, characterization of

the active pharmaceutical ingredient (API), physicochemical properties, pos-
sible route of administration, pharmacokinetic distribution, metabolism,
clearance mechanisms, drug–drug interactions, dosing regimen, safety and
toxicology, antigenicity and hypersensitivity, and pharmacology – including
side effects.2,3 A comparison of these attributes highlights some of the chal-
lenges associated with the development of biologics as drugs. (Table 1.1) It
also begs the question whether new strategies could be discovered to modu-
late drug targets with a different type of small molecules. This is, in essence,
the promise of what allosteric modulators might do.
1.2 Allostery: A 50-Year Old Concept

Broadly, allostery has been defined as an indirect interaction between topo-
graphically distinct binding sites in a protein, mediated by a conformational
change. Monod and Jacob used the term for the first time in the printed
version of the Proceedings of the 26th Cold Spring Harbor Symposium on
Table 1.1 Comparison

of key attributes for small molecules and biologics as
drugs.2,3
Small molecule drugs Biological drugs
Size - Small (single molecule) - Large (mixture of related
molecules)
- Low molecular weight (<1000 - High molecular weight (>1000
amu) amu)
Structure Simple, well defined, inde- Complex (heterogeneous),
pendent of manufacturing defined by the exact
process manufacturing process
Modification Well defined Many options
Manufacturing - Produced by chemical - Produced in living cell culture
synthesis
- Predictable chemical process - Difficult to control from
starting material to final API
- Identical copies can be made - Currently very difficult to
ensure identical copies
- Low cost of goods - High cost to produce
Characterization Easy to characterize completely Not completely characterized in
at chemical and physical terms of chemical composi-
levels tion and heterogeneity
Stability Stable Unstable, sensitive to external
conditions
Immunogenicity Mostly non-immunogenic Immunogenic
View Online
Modulation of Biological Targets Using Allosteric Ligands: Food for Thought 3

Quantitative Biology entitled “Cellular Regulatory Mechanisms” in 1961, in
the general discussion written as a conclusion of the conference. The earliest
appearance of the term “allostery” in a publication listed in PubMed dates to
more than half a century ago.4,5 Since then, the concept has evolved and its
use expanded notably. Today, allosterism is considered an inherent property

of all dynamic proteins and other macromolecules of biological relevance.6
Examples of important drugs exist that are allosteric modulators of diverse
targets such as ion channels, G protein-coupled receptors (GPCRs), and
enzymes. Benzodiazepines, one of the earlier drug classes with major impact
on society, act as negative (flumazenil, 1) or positive (diazepam, 2; flunitraz-
epam, 3) allosteric modulators of gamma aminobutyric acid A (GABAA) ion
channels. The first inhibitors of human immunodeficiency virus reverse
transcriptase enzyme (HIVRT) useful in the treatment of AIDS were nucle-
oside analogs. These compounds act competitively and inhibit the binding
of the appropriate deoxynucleotide triphosphate (ATP, TTP, GTP, or CTP) to
the reverse transcriptase (RT) enzyme. Nevirapine (4) and efavirenz (5) are
non-nucleoside RT inhibitors (NNRTIs). Both nucleoside and non-nucleo-
side RTIs inhibit the same target, the reverse transcriptase enzyme, an essen-
tial viral enzyme which transcribes viral RNA into DNA. Unlike nucleoside
RTIs, which bind at the enzyme's active site, NNRTIs bind allosterically at a
distinct site away from the active site called the NNRTI pocket. Maraviroc (6)
is another antiretroviral drug used in the treatment of HIV infection, which
works through a negative allosteric modulation (NAM) mechanism inhib-
iting the cell-surface chemokine CCR5 receptor. The chemokine receptor
CCR5 is a co-receptor for most HIV strains, necessary for the entrance of the
virus into the host cell. The drug binds to CCR5 and changes its conforma-
tion, thus blocking the HIV protein gp120 from associating with the receptor.
HIV is then unable to enter human macrophages and T-cells. Cinacalcet (7), a
calcimimetic, is a positive allosteric modulator (PAM) of the calcium-sensing
receptor (CaSR), which is activated according to the natural rise and fall of
endogenous calcium ion levels. This drug acts by lowering the threshold
for activation of feedback on the parathyroid chief cells. Trametinib (8) is a
highly selective reversible allosteric inhibitor of mitogen-activated protein
kinase (MAPK)–extracellular-signal-regulated kinase enzymes MEK1 and
MEK2 activity. Compound 8 is an ATP non-competitive inhibitor that binds
MEK at a location adjacent to the ATP binding site. Approved in 2013, it is a
first-in-class oral treatment for metastatic melanoma with BRAF V600 muta-
tions (Figure 1.1).7,8
In addition to these marketed drugs, a number of compounds working
through allosteric mechanisms are undergoing advanced clinical trials at
the time of writing. The serine–threonine kinase AK thyoma oncoprotein
homolog (Akt), also known as protein kinase B (PKB), plays a key role in the
phosphoinositide 3-kinase–Akt–mammalian target of rapamycin (PI3K–Akt–
mTOR) signaling cascade, tightly associated with cell proliferation, survival,
migration, angiogenesis and other activities directly linked to tumor genesis
and progression. The allosteric Akt inhibitor MK-2206 (9) is currently being
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4 Chapter 1
Figure 1.1
Some examples of marketed drugs that work by allosteric mechanisms
at diverse biological targets such as GPCRs, ion channels, and enzymes.
evaluated in clinical Phase 1 and 2 studies on breast, colon/rectal and other

cancers.9 The muscarinic M1 receptor positive allosteric modulator (PAM)
1-(4-cyano-4-(pyridine-2-yl)piperidin-1-yl)methyl-4-oxo-4H-quinolizine-3-car-
boxylic acid (PQCA) (10) has shown in vivo efficacy in a number of preclinical
models in both rodents and non-human primates, suggesting this mecha-
nism may have therapeutic potential for the treatment of Alzheimer's disease
and cognitive deficits.10 The metabotropic glutamate receptor 4 (mGluR4)
PAM Lu AF21934 (11) has been extensively studied in a number of in vitro and
in vivo mechanistic tests. It differentiates from congeners by its remarkable
ability to enhance in vitro agonist concentration–response curves for both,
the mGluR4 homodimer as well as the mGlu2/4 heterodimer, as opposed to
the earlier tool compounds, which are functionally selective for the mGluR4
homodimer (Figure 1.2).11
In some cases, strong support was obtained using X-ray crystallography to
enable the discovery of allosteric drugs. Phosphodiesterase 4 (PDE4) is an
enzyme that hydrolyzes cAMP in cells, and a promising drug target for the
treatment of Alzheimer's disease, Huntington's disease, schizophrenia, and
depression. Drugs treating these diseases by aiming at central biological tar-
gets must cross the blood–brain barrier (BBB) and penetrate into the brain
to exert therapeutic benefit, which restricts the available chemical space for
potential competitive inhibitors. PDE4 inhibitors exist which are cAMP-com-
petitive marketed drugs, but the lack of subtype selectivity is thought to lead
View Online

Figure 1.2
Examples of allosteric modulators used as chemical tools to decipher
the fundamental biology of novel targets and compounds presently
undergoing clinical investigation.
Figure 1.3
Some of the allosteric modulators for which X-ray crystal structures
bound to their biological targets have been reported.
to side effects, including nausea, depression, and weight loss. Studying crys-
tal structures of PDE4 with bound inhibitors exposed the structural basis
of this enzyme’s regulation and inspired, together with mutagenesis and
kinetic studies, the design of subtype-selective negative allosteric modula-
tors of PDE4D with reduced potential to cause the dose-limiting side effects
observed with existing active-site-directed PDE4 inhibitors.12 BPN14770, a
first in class PDE4D NAM (structure not disclosed at present time) is being
developed with support from the NIH Blueprint Neurotherapeutics Net-
work and is the first compound funded by the program to reach a Phase 1
clinical trial.13 Likewise, the recent disclosure of crystallographic studies
with GPCR ligands confirmed their allosteric nature. Notable examples are
the corticotropin-releasing factor-1 (CRF-1) functional inhibitor CP-376395
(12),14 the mGluR5 NAM mavoglurant (13),15 the mGluR1 NAM FITM (4-fluoro-
N-(4-(6-(isopropylamino)pyrimidin-4yl)thiazol-2-yl)-N-methylbenzamide)
(14),16 and the P2Y1 receptor non-nucleotide antagonist BPTU (1-(2-(2-(tert-
butyl)phenoxy)pyridin-3-yl)-3-(4-(trifluoromethoxy)phenyl)urea) (15). The
latter has the peculiarity of being the first structurally characterized selective
GPCR ligand located entirely outside of the helical bundle (Figure 1.3).17
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6 Chapter 1
These last several examples strongly suggest that the use of allosteric
ligands has the potential to help solve druggability issues in areas where
ligands binding at the orthosteric site present challenges, thus providing
a new chemistry modality to deliver therapeutic treatments using small
molecules, with which chemists are highly familiar working. Yet, the pur-
poseful targeting of allosteric sites in proteins that are biological targets of
drug discovery efforts is a relatively recent undertaking in drug discovery
projects.
1.3 llosteric Drugs: The Right Tool at the Right

A
Time
The pharmaceutical industry has witnessed a major change over the last
decade, as it went from working on relatively well-understood biological
targets with clinical validation, where efficacy in the patient population
was expected, to novel biological targets with unprecedented track records
in clinical settings. The reasons for this change are not only scientific,
and include social, political, and financial factors, which are beyond the
scope of this book. The bottom-line is that today, unmet medical needs
and financial incentives dictate the discovery of drugs with enhanced effi-
cacy over existing treatments. A way to achieve this goal is by using novel
mechanisms of action. However, the novelty entails a risky task: demon-
strating clinical efficacy in a broad patient population, usually requiring
Phase 3 clinical studies. Late failures are very expensive, and while they
might be explicated by our imperfect understanding of disease etiology
and flawed replication of human (patho)physiology in the preclinical dis-
ease models used, that is no consolation after a billion-dollar drug devel-
opment exercise yields negative clinical data. The current premise is that
translational sciences will, at least in part, mitigate this risk and enhance
success rates.
Allosteric drugs were envisioned as having the potential to provide two
ways to mitigate the risk of late clinical failure:

1. By providing an alternative molecular mechanism to attack biological
targets (clinically validated or not) that require a different, friendlier
drug-like chemistry space than originally attempted with orthosteric
ligands (e.g., GABA, glutamate or acetylcholine receptors); and
2. Giving novel ways to attack previously intractable targets (e.g., the
calcium sensing receptors or sweet taste receptors; voltage gated
receptors).

Therefore, it seemed reasonable that some of the same biological targets
previously aimed at, and which had been proven recalcitrant to drug discov-
ery efforts using orthosteric ligands, yet not technically invalidated,18 were
given a second life and addressed using allosteric ligands.
View Online
1.4 otential Advantages of Allosteric Modulators

P
Over Orthosteric Ligands… or are They?
A number of excellent publications have discussed in great detail the poten-
tial advantages of using allosteric ligands in drug discovery, including com-

parisons with their orthosteric counterparts.19–23 A review of this literature
consistently points to a variety of factors as drivers to encourage the explora-
tion of allosteric ligands as drugs and chemical probes. These include factors
such as: being easier to achieve selectivity, lack of intrinsic activity, ability to
“dim” endogenous agonist function while preserving spatial and temporal
effects, etc. (Figure 1.4). Some of these initial views have evolved as they were
challenged by experimental data, suggesting a reconsideration of these ide-
alized properties.
Target selectivity is generally thought to be easier to obtain with allosteric
ligands than with orthosteric ligands. This belief would be a consequence
of a highly conserved amino acid sequence in the orthosteric binding site.
Remote allosteric sites tend to be less well conserved, and sufficiently dif-
ferent that selectivity for allosteric ligands may be expected. For example,
when comparing different mGluR subtypes binding the same endogenous
agonist (glutamate), the amino acids forming the binding site are indeed
highly conserved.24,25 Furthermore, these allosteric sites are thought to be an
evolutionary artifact and less sensitive to mutations in terms of the receptor
functional output, as there would be no endogenous ligands binding at such
sites. This would make the design of selective orthosteric ligands somewhat
challenging.
Figure 1.4
Potential favorable attributes supporting the use of allosteric ligands
compared with their orthosteric counterparts.
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8 Chapter 1
However, this thinking may in part be a consequence of how ortho-
steric analogs were conceived in the past. Historically, these ligands were
often designed by constraining the conformation of the endogenous nat-
ural ligand and keeping a similar ligand size. Thus, the same amino acids
are involved in the binding process of both the endogenous ligand and
the putative drug. Indeed, recent work has shown that orthosteric ligand
selectivity may be achieved by making analogs with added substituents,
so that additional amino acids that may no longer be conserved among
receptor subtypes are involved in the binding process. Examples of such
selective ligands are LSP4-2022 (16,26 mGluR4-selective) and LY2812223
(17,27 mGluR2-selective) (Figure 1.5; glutamate backbone shown in color).
Furthermore, evidence suggesting that allosteric sites might play a role in
determining receptor function came from the study of the GABAA receptor,
and the discovery of endogenous ligands binding at the benzodiazepine
site, including oleamides, nonpeptidic endozepines and the protein diaze-
pam-binding inhibitor (DBI).28
Potent and selective adenosine A1R receptor orthosteric agonists and
antagonists have also been discovered and tested in clinical settings for a
number of indications.29 The use of bulky N6-adamantyl substituents on ade-
nosine has led to agonists previously shown to be A1R-selective with respect
to binding affinity at rat receptors.30 Recently, the discovery of a series of
subtype-selective N6-bicyclic and N6-(2-hydroxy)cyclopentyl derivatives of
adenosine as agonists was reported and their A1R/A2R selectivity assessed
based on a modified Saccharomyces cerevisiae strains screening platform. In
addition, the activity at A1R and A3R of a few select analogs which were active
against the A1R in the yeast screen was studied in mammalian CHOK1 cells;
compounds such as 18 and 19 (Figure 1.5) were shown to be highly selec-
tive A1R agonists. Preferred compounds based on potency and selectivity
Figure 1.5
Examples of selective orthosteric agonists for GPCRs of pharmaceutical
relevance.
View Online

Figure 1.6
Structures of M1-selective compounds with mixed ago-PAM profiles.
contained N6-adamantyl substitution in combination with 5′-N-ethylcarbox-

amido or 5′-hydroxymethyl groups.31
In some cases, allosteric ligands have provided a path forward to selec-
tively activate CNS receptors when orthosteric ligands failed to do so. One
such example is the use of compounds 10, 20 and 21 (Figure 1.6), character-
ized as having a mixed agonist–positive allosteric modulator profile highly
functionally selective for the M1 receptor. M1 agonists such as xanomeline
produce beneficial cognitive effects in Alzheimer's disease and schizophrenia
patients. Unfortunately, its therapeutic use is limited due to cholinergic side
effects (sweating, salivation, gastrointestinal distress). These are suggested
to result from nonselective activation of other muscarinic receptor subtypes
such as M2 and M3. However, this theory was refuted as the M1-selective
activators 10, 20 and 21 tested in rats, dogs, and cynomologous monkeys still
elicited cholinergic side effects such as salivation, diarrhea, and emesis.32
This suggests that activation of M1 receptors alone is sufficient to produce
unwanted cholinergic side effects such as those seen with xanomeline.
Another example of an idealized property of allosteric modulators is that
they frequently exhibit little or no intrinsic activity, since their mode of action
is to enhance or inhibit the action of the endogenous agonist.33 The observa-
tion of agonist-independent activity (allosteric agonism) by allosteric modu-
lators is a rather complex phenomenon. Studies have shown that the specific
nature of the biological system under interrogation may play a role in the func-
tional response observed to the same PAM. For example, higher levels of recep-
tor expression in a cell line under investigation may facilitate the observation
of intrinsic activity, as was reported for the case of the glucagon-like peptide 1
(GLP-1) receptor (vide infra).34 Small modifications to the chemical structure of
an allosteric potentiator may provide compounds in the same chemotype with
varying degrees of agonist-independent activity, including none. Thus, dis-
tinct drug target product profiles may be defined. Allosteric agonists or “ago-
PAMs” are compounds with intrinsic activity independent of the endogenous
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10 Chapter 1
ligand. On the other hand, “pure PAMs” show activity only in the presence of
the orthosteric agonist and no activity in its absence. In any case, medicinal
chemistry optimization to a preferred target product profile is feasible.35
Allosteric ligands are also thought to allow fine tuning of functional
responses. While this may be the case for properly designed and character-
ized PAMs, most notably for mGluR5 PAMs,36,37 it is also possible to achieve
super-physiological functional responses, above what the endogenous nat-
ural system may deliver.38 This design attribute may be an advantage in
diseases where the tone of the endogenous agonist is high but the receptor
functional response needs augmentation.39
As acknowledged by Dougall and Unitt, the “potential advantages of
allosteric modulators remain largely theoretical as very few such agents have
to date reached the market”.40 About a decade into conducting research with
the intent to engineer certain attributes into allosteric drugs using struc-
ture–activity relationships (SAR) as has been done with orthosteric ligands,
it seems prudent to maintain some level of skepticism regarding the extent
to which this potential has been realized.
1.5 Looking Under the Hood

Once the idea of modulating the functional activity of a biological target
using allosteric drugs found support in reliable early experimental data, it
also became clear than the concept was more complex than initially thought.
Empirically, differences could be found between developing SAR for allosteric
compounds that are inhibitors (NAMs) or enhancers (PAMs) of biological tar-
get function. Furthermore, subtler aspects further differentiate different types
of allosteric enhancers. For enzymes, K-type modulators affect the affinity of
the substrate, while V-type modulators affect the catalytic rate. Distinct cases
(Type II, Types Ia and Ib) generate unique kinetic signatures which may be of
diagnostic value.41 For membrane-bound targets (e.g., GPCRs, transporters),
some compounds may act by enhancing the affinity of the orthosteric ligand
(Kd), others by increasing the efficacy at the receptor (Emax), or by acting as
allosteric agonists activating the receptor in the absence of orthosteric agonist
(e.g., Figure 1.7). In practice, compounds with a combination of these modes
of action are often encountered.42 Indeed, examples of allosteric modulators
exist which enhance the binding affinity of the orthosteric ligand (attribute of
a PAM) while reducing the receptor efficacy (attribute of a NAM).43
One of the models used to describe the effect of an allosteric ligand on
the functional response elicited by the action of an orthosteric ligand at a
receptor is the Operational Model.44 Mathematically, this model can be rep-
resented by eqn (1.1), where pKA and pKB are the affinity of orthosteric and
allosteric ligand for the free receptor, respectively; α is the affinity cooperativ-
ity factor, β is the efficacy cooperativity factor, τA and τB represent the agonist
and modulator efficacy, and n is a scaling factor.45 Indeed, the simulations
shown in Figure 1.7 were generated using this equation. Recommendations
for its proper application have been discussed.46
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Figure 1.7
Graphical depiction of concentration–response curves for different
types of modulators of GPCR function, exemplified for the metabo-
tropic glutamate receptor 4 (mGluR4). Simulations computed using the
following parameters: Em = 268; pKA = 5.5; pKB = 6.5; τA = 0.7; n = 1.5.
Ligand concentrations are as indicated in the legends. A: α = 100; β = 1;
τB = 0. B: α = 1; β = 3; τB = 0. C: α = β = 1; τB = 0.5. D: α = 1; β = 0.01; τB = 0.


Em  A  A  K B   B   B B K A 
n
E
 A  K  K A K B  K A B    A B   A  A  K B   B   B B K A 
n n
B
(1.1)

A protocol known as “triple addition” has become broadly used in
allosteric drug research.47 This methodology enables the fast and efficient
screening of compound libraries in projects seeking to identify novel mod-
ulators of receptor function by exploring in a single assay the effects of
compound alone (which identifies new agonists, orthosteric or allosteric),
Another random document with
no related content on Scribd:
they would be in one’s own house. Of course the American cars
have also a stove at each end.
CHAPTER XXI.
BOSTON IS THE HUB OF AMERICA—MR. TICKNOR—
PROFESSOR ROGERS AND THE TECHNOLOGICAL—MR.
NORTON—PROFESSOR AGASSIZ—MR. APPLETON AND MR.
LONGFELLOW—MR. PHILBRICK—A GRAMMAR SCHOOL
COMMEMORATION—HUMILITY OF THE BETTER LITERARY MEN
OF BOSTON—REGRET AT LEAVING BOSTON.
Boston is the hub of the world. So say those who,
not being Massachusetts men themselves, are Boston the Hub
disposed to impute extravagant pretensions to the of America.
good old Puritan city. The hub, in the language of
America, is the nave, or centre-piece of the wheel, from which the
spokes radiate, and on which the wheel turns. As the Americans
make with their hickory wood the best wheels in the world, they have
some right to give to one of the pieces a name of their own. But,
however, Boston need not quarrel with the saying. Nations, like
individuals, are generally governed by ideas, and no people to such
a degree as the Americans: and the ideas which have governed
them hitherto, have been supplied from New England. But
Massachusetts has been the wheel within New England, and Boston
the wheel within Massachusetts. It has therefore been the first
source and fountain of the ideas that have moved and made
America, and is, in a high and honourable sense, the hub of the New
World.
Among the celebrities of Boston with whom I was so fortunate as
to become acquainted, and to see in their own houses, I will name
first Mr. Ticknor, the author of the well-known ‘History of Spanish
Literature,’ himself now the father of American literature. His
reminiscences of the history and society of his own country, and
largely too of English literary society, for the last fifty years,
contribute very much to enrich his conversation. I have a grateful
sense of his hospitality, and of the other ways in which he assisted in
making my visit to Boston most agreeable.
My next acquaintance was Professor Rogers, the head of the
Technological Institute of Boston. A great deal has been spent by the
city on the building in which this Institute is housed, and in providing
it with an able staff of professors; and it has proved thoroughly well
adapted to the teaching of all the different branches upon which it
undertakes to give instruction. These are Physics, Chemistry,
Mathematics, Mechanics, and Drawing, particularly as required by
machinists, engineers, builders, and architects. Its objects are
entirely practical; but it would be a gross mistake to depreciate them
on that account. The knowledge imparted here is necessary for
certain trades and professions; and it is better that this knowledge
should be communicated well and correctly, than that it should be
picked up imperfectly. It is better that those who carry on any
business that is based on scientific principles should be familiar with
its principles, than that they should go through life working merely by
the rule of thumb. In the programme of the Institute Professor
Rogers’s department is Physics; but in fact the Technological
Institute is Professor Rogers, and Professor Rogers (for he is so
devoted to it that it has become a part of himself) is the
Technological Institute, plus a great deal that is good, and refined,
and generous.
I spent an evening with Mr. Norton, the editor of
the ‘North American Review.’ I was much pleased Literary Society
with all that I saw of Boston society, but this at Boston.
evening at Mr. Norton’s recurs to my recollection
with especial distinctness. He, as the editor of the leading Review of
the New World must for many years have had his finger on the
literary pulse of America, and must know better than any other
person what American writers can do, and what the American public
appreciates. I was glad to hear that Mr. Norton contemplated
spending twelve months in England with his family, though I
regretted that he should find that a year of rest and of change of
climate was necessary for him. It seemed to me, that both he and
Professor Rogers were much overworked, and were also suffering
from the withering aridity of the climate. A great part of the
population of New England appears to be affected by the same
cause—their vital organs are going through a process of desiccation.
I trust that both these good and true workers in the literary society of
Boston will before long be indebted for their restoration to health and
strength to the moister and more merciful climate of the old country.
I was sorry that the shortness of my stay prevented my accepting
an invitation from Mr. and Mrs. Agassiz. They are persons of whom it
is impossible to know a little without wishing to know a great deal
more. They had lately returned from their explorations in Brazil, but
more especially in the Valley of the Amazon. The popular narrative of
the expedition (for it was composed of several persons) was written
by Mrs. Agassiz, and has just been published. The more detailed
and scientific account, by Mr. Agassiz, is eagerly expected. His
character appears to be a most singularly transparent one. He has
strong social instincts. In society he is evidently in his true element.
But all the while, by the side of this keen enjoyment of society, you
see that his soul has been constructed for making those discoveries
in physical science, and acquiring those new ideas, he has so much
happiness in presenting to the minds of others. His rich genial
conversation and ready sympathies are worthy of the high position
he holds in the scientific world.
To Mr. Thomas G. Appleton—the first American, I believe, who
crossed the Atlantic in his own yacht—I am indebted for several
kindnesses; among them for his taking me to his brother-in-law, Mr.
Longfellow, who resides at Cambridge, about three miles from
Boston. Mr. Longfellow’s house is the oldest in the place, and has a
good deal of curious antique carving and panelling. This is as it
should be, for one can hardly imagine a poet living in a new, square-
built, brick house, without a tradition or association.
In mentioning those whose names are public
property, from whom I received kindnesses at Young Ladies’
Boston, I must not omit Mr. Philbrick, the Recitations.
Superintendent of Schools for the city. He allowed
me to spend a morning in the Poplar Street Primary School, which
was quite a model of its kind. It contained 300 children, divided into
six grades. With few exceptions, they all come at the age of five, and
leave at eight. He also took me with him to the yearly
commemoration of the Adam Street Grammar School, in a distant
suburb of the city. This is a mixed school for boys and girls, or rather
for young ladies, for some of the latter were certainly not less than
eighteen years of age. There were present on the occasion the
superintendent, some assistant superintendents, or committee-men
—I forget which was their title—and many of the parents of the
children. The work consisted in recitations, singing, and reading
extracts from a periodical written by the pupils and published in the
school. The reciting was fairly done. No timidity was shown by any
young lady who ascended the platform; but there was no boldness,
or anything in any way unpleasing. There was only a degree of easy
self-possession that would have been unusual in English ladies of
any age. I mention this because the impression left on Mr. Fraser’s
mind by exhibitions of this kind appears not to have been favourable.
As soon as the business of the day was over, Mr. Philbrick, being the
chief official in the city connected with education, was called upon by
the head-master to make a speech, or, as it is called in America, to
deliver an address. After speaking for about ten minutes, he
concluded by telling the company who I was, and with whom I was
acquainted in the city, adding that he hoped I would give those
present the pleasure of hearing me say something. I was a little
taken by surprise at this summons, the heat of the room having
almost put me to sleep. Otherwise one ought always to be prepared
for such requests, because in America you may be quite sure that
they will always be made. It is one of their institutions.
One hears a great deal about what is described as the arrogance
and conceit of Americans. I never met with anything of the kind,
except among classes which with us are generally too ignorant to
know much, and too apathetic to care much about their own country.
The upper classes are proud of their country, as they ought to be,
and that is all. At Boston, however, I was struck, not with the
arrogance and conceit, but with the humility of Americans. I am
speaking now of the literary class; and I think the phenomenon is to
be accounted for in the following way. These New Englanders are
the most observant and the most receptive of the human family, and
it is the first thought of all among them who have literary aspirations
to travel in England and on the European continent. These are to
them the Holy Land of thought. It is here that all the branches of
literature, and all the departments of science, originated and were
matured. All the creations of fancy, all the lessons and examples of
history, all the familiar descriptions of outward nature, and of human
emotions, come from this side. Here, then, are the shrines which the
literary men of the New World must visit with the staff and in the spirit
of a pilgrim. They feel an influence which their fellow-countrymen do
not feel. But besides this, because they are New Englanders, they
note and weigh every idea and practice they find in European
society; and everything that approves itself to their understanding,
they adopt readily and without prejudice. This is the reason why
travelled New Englanders are generally so gentlemanly and
agreeable. They understood what they saw abroad, and they have
acknowledged to themselves that they have learnt much that they
never would have known anything of if they had stayed at home.
This, which is true of all, is doubly true of their literary men. One of
the leading writers of New England described to me the craving that
he felt for intercourse with minds cultivated as they are only in
Europe. There only, in his opinion, men had time to think; there only
had the critical faculties been trained; there only could you meet with
broad and profound views on questions of literature, history, or
policy. The whole of the literature of America was but a rechauffé of
that of England, France, and Germany.
I regretted the necessity which obliged me to
leave Boston before I had seen as much as I Humility of the
wished of its society. I did not feel in this way Leading Literary
because it more nearly resembles European Men.
society than is the case in any other city of the
Union—for one does not go to America to see what can be seen at
home—but because I wished to know more of some with whom I felt
that it would be a happiness afterwards to be acquainted, and
because I was desirous of using every opportunity for arriving at
some distinct conclusions as to the tendency of opinion and thought,
more particularly religious thought, in the New World.
CHAPTER XXII.
AMERICAN HOTELS—WHY SOME PEOPLE IN AMERICA TRAVEL
WITHOUT ANY LUGGAGE—CONVERSATION AT TABLES-D’HÔTE
SHOULD BE ENCOURAGED—THE IRISH, THE AFRICAN, AND
THE CHINESE—CAN A REPUBLIC DO WITHOUT A SERVILE
CLASS?—WHAT WILL BE THE ULTIMATE FATE OF THESE THREE
RACES IN AMERICA—NO CHILDREN—MOTIVES—MEANS—
CONSEQUENCES—WHY MANY YOUNG MEN AND YOUNG
WOMEN MAKE SHIPWRECK OF HAPPINESS IN AMERICA—THE
COURSE MANY FAMILIES RUN—AMERICA THE HUB OF THE
WORLD.
During the week I was at Boston, I dined for the last time in an
American hotel; for the fortnight I afterwards spent in my second visit
to New York, I passed in the hospitable house of Mr. Henry Eyre, a
brother of the Rector of Marylebone, and a worthy representative of
Englishmen in the commercial capital of America. With this
exception, at the close of my tour, I made it a rule, from which I never
departed, to decline all invitations to stay in private houses. My
reason for doing this was, that I might come and go as I pleased,
and have my time always at my own disposal. This gave me
abundant opportunities, as my travels extended over 8,000 miles of
American ground, for forming an estimate of their hotels and hotel
life. With a few exceptions here and there, in some of the large
eastern cities, the hotels are on the monster scale, and managed on
the American system. The exceptions are called English, or
European hotels, and their speciality is that you only pay in them for
what you have. On the American system you pay so much a day for
board and lodging; liquors and washing being extras. That the
American system is the cheapest and most convenient, is
demonstrated by its universality. The few exceptions that exist have
to be inquired after and sought out. A traveller will also avoid them,
because he is desirous of seeing the manners and customs of the
people; and these can nowhere be seen so readily, and to such an
extent, as in the monster hotels. They are a genuine production of
the soil, are in perfect harmony with American wants and ideas, and
are all alike.
Their distinguishing features are that the greater
part of their guests are not travellers, but lodgers American
and boarders; and that they have one fixed charge Hotels.
for all, of so many dollars a day. The dearest I
entered was the Fifth Avenue Hotel at New York, which charged five
dollars a day; the board consisting of five such meals as no hotel in
England or Europe could supply without bankruptcy. They are
enabled to do this, because they have to supply these meals for
several hundred persons. And they have this large number of
guests, because multitudes of families, that they may escape the
expense and annoyances of house-keeping, live in the hotels, and
multitudes of men in business, keeping only a counting-house or a
store in the city, do the same. The cheapest I was ever in charged
three dollars and a half a-day. The service is so well organised in
these hotels, that you may come or go at any hour of the night; and
you can get your linen washed and returned to your room in a few
hours. While dressing one morning at the Sherman House at
Chicago, I sent out my linen to the laundry; on going back to my
room at half-past eleven, I found that it had been washed and
returned. This rapidity with which the washing of linen is performed
in America enables one to travel with much less than would be
requisite in Europe; and it explains why one often sees people
travelling in America with no more than they can carry in a little
hand-bag, called, in the language of the country, a satchel.
It does not, however, explain why some people in America travel
with no luggage at all. Some of those whom I observed entering and
leaving the cars in this light and unimpeded fashion, told me they
had adopted the system because the work of the washerwoman had
been advancing among them, not more in rapidity than it had done in
costliness, so that it was now cheaper to get a new article,
something at the same time being allowed for the old soiled one,
than to send one of the same species to the laundry of the hotel. By
acting on this idea they had escaped the necessity of taking with
them relays of linen. I suppose this system must be an
encouragement to the trade in paper shirt-collars. The difficulty as to
razors, brushes, and combs, is easily met by the provision made in
the barber’s shop of every hotel. The Americans are full of original
ideas, and they are very great travellers; it was therefore to be
expected that they would be the first people to organise and perfect
a system of travelling like the birds of the air.
The Americans having now revolutionised
throughout the whole country the method of Conversation at
serving hotel dinners, passing at one step from Meals.
what was the worst method of all to what is greatly
in advance of the practice in this matter of all other nations, I would
venture to suggest another change in a matter of still greater
importance. It is evident that civilisation would have been quite an
impossibility, if people had not met together at meals for the purpose
of conversation. This alone rescues the act of taking one’s food from
its animal character, and associates it with the exercise of our moral
and intellectual qualities. If we do not meet together, and converse,
and exchange thought, and cultivate courtesies, our meals differ in
no respects from the act of a horse or of a pig taking a feed. It is a
strange mistake to suppose that there is anything intellectual or
spirituel in hurrying through one’s meals. The truth of the matter is
exactly the reverse. To tarry at the table for the purpose of
conversation makes every meal a school for the intellect, and for the
promotion of the domestic and social graces. The savage hurries
over his meals because he is a savage, morally and intellectually
near of kin to the brute. If he could tarry over his meals he would
have ceased to be a savage. All ancient and modern nations that
have been highly civilised have acted instinctively on this idea. The
Attic symposia, as well as the French petits soupers, rested upon it.
Suppose meals are to be silently hurried through, they become mere
brutish acts of eating and drinking, which any animal can perform as
well as ourselves, and in much less time too. It is here that the
Americans have a grand opportunity, in their widely diffused and
generally practised hotel life, of which, it seemed to me, they were
not availing themselves. You will see people day after day sit down
to the same table, take their food in silence, and leave the table
without a word having been spoken. You may observe several tables
occupied at the same time in your neighbourhood, and there shall be
no conversation going on at any one of them. Those who sit at them
appear to be entirely occupied either with their own thoughts or with
attention to what they are eating. But it would make hotel life far
more agreeable, and impart to it a far greater amount of civilising
power, if it were the rule that people who meet at the same table
might converse with one another, without any previous
acquaintance, and without any necessity for subsequent
acquaintance. Let it be understood that on such occasions
conversation is the correct and the civilised thing.
No American will ever undertake any of the lower forms of labour
—very few of the men before the mast in American ships are native-
born. The class of agricultural labourers is unknown among them.
What labour they have of this kind is supplied by immigration. No
American would become a footman or hotel waiter. Their railways
were not made by American navvies. In the North all the lower kinds
of labour—but which, though they rank low as employments, are still
necessary to the well-being, even to the existence of society—have
hitherto fallen to the lot of the Irish, English, and German immigrants.
Their place has been taken in the South by the blacks, and in the
Pacific States by the Chinese.
This suggests two very interesting questions.
The first is, Can a republic be carried on without a The Future of
servile class? What would be the state of things in the Servile
the American Union if it were deprived of the Classes.
services of the Irish, the blacks, and the Chinese?
Of course the loss would be much felt, and would very much retard
the progress of the country; but I do not think that it would be a loss
that would be irremediable and ruinous. As soon as the country
begins to fill up, there will begin to appear in America the class that
has existed in every country in the world, composed of those who
have neither property nor a knowledge of any trade (which can
seldom be obtained by those who have no property), and who
therefore have nothing to live upon except their power of doing rude
and unskilled work.
The other question is, What will be the future in the American
Republic of these three races? The African, we may be sure, will
either die out, which is most probable, or become a low caste, the
pariahs of the New World: retail trade and a few of the lower kinds of
labour and employment will be open to them. They will possess civil
but not political rights. The Irish will be absorbed into the general
population; and so one may speculate to what extent this will affect
the American character. The Chinese can never be absorbed. What
therefore will be the position that they will occupy in the Union fifty or
a hundred years hence? Hitherto only one State has been open to
them, that of California. Can anything be inferred from the position
they have created for themselves in that State? I think we may be
safe in supposing that, as they have already crossed the Pacific to
the number of sixty thousand, when by the completion of the Pacific
Railway the whole of the Union is thrown open to them, they will not
remain cooped up in California. In a few years I believe they will be
found in New York, and in all the large cities of the west and east.
Voltaire said that the true wall of China was the American continent,
the interposition of which saved it from European invasion; but it
appears now that the American continent is the very point at which
the European races will be invaded by the long pent up population of
China. To what extent will this invasion be carried? and what
consequences will result from it? One thing, I think, may be foreseen
—the Americans will not admit these Asiatics, aliens in religion as
well as in race, to political equality with themselves.
A recent writer on America has informed us that there is a
disinclination among the wives of the luxurious cities of the Atlantic
seaboard to become mothers. I found, after enquiry made
everywhere on the spot, that this indisposition to bring up children is
not confined to the wives or to the cities this writer’s words indicate,
but is participated in, to a large extent, by the husbands, and is
coextensive with the American Union. It is just as strongly felt at
Denver, two thousand miles away, as at New York, and results in
almost as much evil at New Orleans as at Chicago.
The feeling—or, it might be said, this absence of natural feeling—
may easily be explained. The expenses and annoyances of house-
keeping are in America very great; and young
couples, except when they are rich—and such Limitation of
cases must always form a small minority— Offspring.
generally escape them by living in hotels. Hotel
living is always according to tariff, so much a week for each person.
To a couple living in this way, and barely able to find the means for it,
the cost of every additional child can be calculated to a dollar, and is
seriously felt. As long as they are without children they may get on
comfortably enough, and go into society, and frequent places of
amusement. But if encumbered with the expense of a family, they
will have to live a far quieter and less gay life. They cannot give up
their autumn excursion, they cannot give up balls, and dresses, and
concerts, and carriages. Therefore the husband and wife come to an
understanding that they will have but one child, or that they will have
no children at all.
Another reason for the practice, which would appear to affect the
wife only, but which has frequently much weight with the husband
also, is that the American lady’s reign is not, under any
circumstances, a long one. She has generally considerable personal
attractions, but the climate and the habits, of living are so trying that
beauty is very short-lived. The young wife therefore argues, ‘My
good time will under any circumstances be short; why, therefore,
should I prematurely dilapidate myself by having half-a-dozen
children? And indeed what would that come to, but that I should
have no good time at all, for the whole of it would be given up to the
nursery? And by the time this would be over, I should be nothing but
a wreck; my good looks will have disappeared, and I shall have
fallen into premature old age.’
I met with husbands who themselves justified the practice on
these grounds. They did not wish to have their wives, during the
whole period of their good looks, in the nursery.
There is no secret as to the various means resorted to for carrying
out these unnatural resolutions. They are advertised in every
newspaper, and there are professors of the art in abundance,
judging from the advertisements, in every city. There is one large
establishment in the most fashionable street in the city of New York,
from whence the great high priestess of this evil system dispenses
her drugs and advice, and where also she receives those who need
her direct assistance. These things are so notorious and are so
much talked of, that one is absolved from the necessity of being at
all reticent about them.
No one, of course, would suppose that any practice of this kind, so
abhorrent to our best natural instincts, could become universal: nor
is it so in America: many denounce it. But still it spreads; and we
cannot expect that it will die away, as long as the motives which
prompt it continue to be felt as strongly as they are at present.
I will note one of the evil consequences of the practice. When
those who have acted in this unnatural way are no longer young, and
the motives which prompted their conduct have ceased to have any
weight, the husband and wife find that there is no tie between them.
They have no reason to respect each other. Each condemns the
other, and is in the other’s presence self-condemned. And this is one
of the causes of the numerous divorces which so much astonish
those who look into the social conditions of American life. Nature and
our common moral sense will avenge themselves for such outrages.
A stranger travelling in America is not likely to
receive letters to any except prosperous persons, Life-wrecks in
and so, unless he is on his guard against it, his America.
personal experience is likely to be confined to the
bright and splendid side of society. But from the observations and
enquiries I made, I came to the conclusion that there is no country in
which the proportion of those whose destiny it is to suffer complete
eclipse of happiness is so great as in the United States. Among men
one chief cause of this appeared to me to be the irresistible
attraction a life of heartless dissipation has for multitudes of young
Americans. Why is this so? I believe their theory of social equality is
responsible for some of it. They have a fatal craving to appear as
fashionable, and to enjoy life as much as their wealthy neighbours.
But I do not suppose that this will account for everything. After all,
the careers that are open to city-bred young men are very limited.
Practically for them there is not much beyond the counting-house
and the store. Farming, the great employment of the country, is
repulsive to them; and the ranks of the law are generally recruited
from the hard-headed and enterprising sons of farmers. But be the
cause what it may, there stands the fact that in the large American
cities, and of course nowhere to such an extent as in New York,
there is to be found a large class of young men of very limited
means, who are living dissipated lives, and whose great aim is to
appear fashionable—a detestable word, and a vulgar and unmanly
idea, of which we in the old country have not heard much since the
times of the Regency.
The case of the women who fail in life is more sad than that of the
men, because, while they have less control over their own destinies,
the failure in establishing a happy home is to them the failure of
everything. The impracticable theory of social equality, I was again
led to believe, was frequently the cause of such failures. These
young women have been brought up in precisely the same way as
their more fortunate sisters, at the same or at similar schools. This
makes, in after life, the distinctions that meet the eye—of dress,
equipage, and position—enter like iron into the soul; and so the
determination to appear as others do becomes the rock upon which
the happiness of many is wrecked.
These, however, are matters upon which a stranger will be very
distrustful of his own observation, and will always hold himself open
to correction from those upon the phenomena of whose social life he
is commenting.
I will append to the foregoing remarks on the
way in which many young persons in American The Hub of the
cities make a wreck of their life’s chances, an World.
outline of the course I observed many families ran
in America. The son of a farmer, we will say in Massachusetts, has
some ambition. There is no field for ambition in New England
farming. He therefore goes to Boston, or some commercial town,
and becomes a lawyer, or a merchant, or a professional man of
some kind or other. He rises to wealth and distinction, which are not
so often secured by the city-born as by those who have the energy
and vigour of new blood fresh from the country. He leaves his family
well off. They never go back to the country. If any of the children
have the energy and vigour of the father, they do not enter into
business in Boston, but go out to the west, and help to build up such
places as Chicago and Omaha. But if, as is generally the case, they
have not energy and vigour enough for this, they go to New York, or
some large city, where refined society and amusements are to be
had. Some travel much, and take life easily. Some occasionally enter
into political life. They marry city ladies, who are possessed of great
refinement, but have very bad constitutions. They have two or three
children with long thin fingers and weak spines. There is no fourth
generation.
An Englishman cannot feel towards Americans as he does
towards Italians or Frenchmen. Wherever in America he sees a
piece of land being cleared and settled, or a church or a school
being built, he looks on as if something were being done by and for
his own countrymen. There is, however, one thing the evil effects of
which he regrets to see everywhere, and that is the restrictions by
which his American brethren are everywhere limiting trade and
production. As he goes through their vast continent, and visits region
after region, each capable of producing some different commodity
the world needs, in sufficient quantities for the wants of all civilised
nations, he rejoices at the greatness of their prospects, at the
contemplation of all the wealth that God has given them. And he
feels certain that the day cannot be very distant when they
themselves will make the discovery that a dollar’s worth of wheat, or
maize, or cotton, or tobacco, or pork—and, when the plains shall be
turned to account, of beef, or mutton, or wool—is exactly equal in
value to a dollar’s worth of manufactured goods, and two dollars’
worth is exactly twice the value, and a hundred dollars’ worth is of
exactly a hundred times the value. And that when they shall have
made this discovery they will strike off the fetters from trade and
production, and by a single vote of their legislature increase the
national wealth no one can foresee how many fold; and thus make
themselves, what their vast and all-producing country, commanding
both oceans and placed midway between Europe and Asia, is only
waiting to become—the hub of the world.
CHAPTER XXIII.
ON AMERICAN COMMON SCHOOLS—CONCLUSION.
It was my practice, wherever I was staying, to visit
some of the schools of the place. I have spoken of American
several of these visits in the foregoing pages. I will Common
now give, collectively, the conclusions at which I Schools.
arrived on the subject of education in America,
after an actual inspection of schools, and much conversation with
persons interested and engaged in educational work in every part of
the Union, with the exception of the new States on the Pacific coast.
We have had the American Common School system held up
before us for many years for our imitation. We have been told that,
compared with it, our own efforts in the cause of education are
discreditable and contemptible. We have been urged to look at what
they are doing; to consider how highly they tax themselves for this
purpose; to admire the effects of this system, as seen in a people,
the whole of whom are now educated and intelligent. Of course the
inference always is, that the best thing we can do is to go and do
likewise. These are vague generalities, which an acquaintance with
the subject will in some respects largely modify.
First, I demur to the statement that Americans do tax themselves
so highly for the purpose of education. It would be much nearer to
the truth to say that there is no people on the face of the earth who
educate their children so cheaply as the Americans; and therefore
much more in conformity with the facts of their case, and of ours in
this matter, to urge us to endeavour, by considering their example, to
cheapen education amongst ourselves. I have now before me the
most recent report of the Board of Education for the city of New York.
It is for the year 1866. From this it appears that, taking together all
the common schools of the city, the Primary, the Grammar, the
Coloured, the Evening, the Normal, the Corporate, and the Free
Academy, now the College of the City of New York, there are
227,691 children and young persons receiving education at a total
cost for everything—including rents, purchases of sites, building,
repairs, and salaries of officers of the board, as well as of the
teachers—of 2,420,883 dollars, or about 30s. a head. Are the
children of any city in England educated as cheaply? These schools
educate a considerable proportion of the children of the higher class,
that is the professional men and merchants; speaking generally, all
the children of the middle class, that is of the tradesmen; and as
many of the children of the artisan and unskilled labouring class as
their parents choose to send. This 30s. is a high average for
American cities. I believe it is higher than any other in the United
States. Tradesmen with us pay about 35l. a year for a child kept at a
boarding-school, and about 15l. a year for the education given at day
schools. In the great city of New York about 400,000l. a year is spent
on the education of all classes, plus the cost of the few of the upper
class who are sent to private schools. How much more, we may ask,
is spent here on the education of 227,691 children of the different
ranks in life of these New York children? There can be no doubt but
that our unmethodical system, notwithstanding our numerous
foundations, costs us much more than their system costs the
Americans. Ours is the costliest educational system in the world;
theirs the most economical.
This is still more apparent when we pass from
the towns to the country. There the cost frequently Cheapness of
falls below 10s. a head. The children educated in American
these schools are those of the proprietors of the Schools.
land, but who cultivate it themselves as well as
own it. Are the children of this class, in any part of the world,
educated for so small a number of shillings a year? Why, in New
York you have to pay as much for a pair of gloves, and more for a
bottle of wine. In Illinois, one of the richest States in the Union, and
whose population is probably better off than any equal number of
people in any other country, the average cost for the children of the
whole State is little more than this 10s. a head. And in
Massachusetts, the State in which attention has been most carefully
and for the longest time directed to the subject, and where
everything is done that is thought necessary, the average for the
town and country children actually at school is only 25s.
The fact is simply this. The rural population in America is the most
homogeneous in the world. It is composed entirely of farmers, and of
their sons and brothers who are the professional men and
tradesmen of the district. Landlordism and tithes are unknown: so
there is no one above the farmer-proprietor, and from New York to
San Francisco there is no such class as our agricultural labourer,
and so there is no one below the farmer. Now, how can a number of
families of this kind, who are all completely on a footing of social
equality, and also, if the word may be allowed to pass, pretty nearly
of possessive equality, best educate their children? In a new country
there are no foundation schools and few private ones—that is to say,
to all practical purposes, no schools at all. There is, therefore, but
one way of getting what they want—that is, by establishing schools
of their own; and this can only be done by taxing themselves. There
is no great sagacity shown in seeing this; and, as a matter of fact,
everyone in America sees it. It is not seen more clearly in
Massachusetts than it is in Ohio, or in Ohio than in California, or in
California than in Colorado. I understood, indeed, that the schools of
California (I had no opportunity of examining them myself) are the
best in the Union; and the statement is not incredible, for the
Californians are a people who will have nothing that is second-rate.
One can hardly get now at any price a real Havana cigar in London
or Paris, because the people of San Francisco will always pay the
best price for the best thing. And in the territory, for it is not yet the
State of Colorado, in the mountains, at Denver, and on the plains,
two thousand miles away from Massachusetts, I saw the common-
school system at work, in places where Judge Lynch is still the
guardian of society in its infancy. No motive of patriotism or
philanthropy can act in this universal and unfailing way. It can only
be done by all, and in the same way by all, because it is obviously
for the interest of all to do it, and because they could not get what
they want in any other way. It is not forced on the rural townships by
the general government of the State, but it permits them to tax
themselves, if they please. And as they happen to raise the money
they require by a tax, it becomes easy to ascertain exactly what the
amount is; and the figures, as they include all that is paid for
educating the children of a large State, appear to represent a very
considerable sum, although, when it is looked into, it is seen to be
the cheapest work of the kind that is anywhere done. The State of
Illinois has now perhaps 10,000 schools, not far from 20,000
teachers, and about 600,000 scholars. The aggregate sum with
which the people tax themselves for these schools and scholars
appears very great, but in reality there are no other 600,000 scholars
so cheaply educated. Our two schools of Eton and Harrow cost the
parents of the children educated at them more than these 10,000
schools cost the people of Illinois.
And when we come to look into the working of
the American school system in the cities, we see The Mother of
that nothing could be done without the motives I the Invention.
have spoken of, as never failing to bring about one
uniform result in the country. The artisans, and tradesmen, and small
professional men know that this is the best and cheapest way for
them to get the kind of education they desire for their children. They
are the great majority, and so of course the thing is done. There is a
general tax, and common schools are established. And, as they
have some advantages besides that of cheapness, they are used by
many of the upper class—I mean merchants, bankers, and
successful professional men, especially those who wish to stand well
with the democracy. None can be excluded from the schools (indeed
no one wishes it), and so they are open to the lowest class of the
town population, with which there is nothing to correspond in the
country. In truth, so far from wishing for any exclusion, great efforts
are made to get hold of the children of ignorant and vicious parents,
both from philanthropic and from self-interested motives, because in
cities where every man has the suffrage, a vicious and ignorant
population is doubly inconvenient and dangerous. Hitherto, however,
the Americans have hardly succeeded in the towns better than we
have, in their efforts to bring these children into their schools. At New
York they have supplemented the common schools with a system of
industrial schools, intended especially for those who would never
enter the common schools. But all that can be said of them is, that
they have met the evil they were intended to remedy to some small
extent. At Chicago, I was told by the able superintendent of the city
schools that there were 20,000 children in that city who frequented
no school. And this is a growing evil in all the great cities of the
Union.
The Americans, then, very wisely (in fact they
could do nothing better, perhaps nothing else) Abundance of
have established, in the country and in the cities, Good Teaching
common schools for their own children. What we Material.
are called upon to do is a totally different thing; and
this I insist upon as another great distinction between what they have
done, and what we are doing, in this matter. We have to establish
schools for other people’s children. With them those who pay for the
school profit by it. With us those who will pay for the school will never
derive any advantage from it. The point for us to settle is, How shall
farmers and landlords be made to tax themselves for the education
of labourers’ children; and how shall the householders, and
professional men, and tradesmen of a town be made to tax
themselves for the schooling of the children of artisans and
operatives? The Americans may be left to manage the business
themselves, for it is their own affair. But we cannot: with us the law
must be imperative, not permissive, and constant supervision will be
needed; and to secure this right of supervision, it will probably be
found necessary that the State should itself contribute largely
towards the maintenance of the school.
The Americans possess an advantage in their schools to which
there is at present no prospect of our attaining. The teachers of our
elementary schools are taken from the humblest and most
uneducated stratum of society, and have to be trained for their work.
They have none of the traditions of mental culture, and their
sentiments must in a great measure be those of their relations and
friends. The humbleness of their origin does also considerably
detract from the social position it would be desirable they should
occupy. In America a like origin would not have the same effect; but
here the daughter of a labourer or mechanic has not the influence
with the parents of the children, or the respect shown to her, which
would be readily conceded if she were the daughter of a farmer or

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Allosterism in Drug Discovery

RSC Drug Discovery Series No. 56

Print ISBN: 978-1-78262-459-2

© The Royal Society of Chemistry 2017

All rights reserved

Published by The Royal Society of Chemistry,

Registered Charity Number 207890

For further information see our web site at www.rsc.org

RSC Drug Discovery Series No. 56

allosterism is broadly seen in nature, we are presenting examples from the

With admiration, to all drug hunters who pursue Nature's truths

1.1 Drug Discovery in the Early 21st Century  1

Chapter 2 Identifying and Quantifying Allosteric Drug Function  24

2.1 Introduction: Receptor Allosterism  24

RSC Drug Discovery Series No. 56

Chapter 3 Targeting Catalytic and Non-Catalytic Functions of

Chapter 4 Molecular Biology Techniques Applied to GPCR Allosteric

Chapter 5 Examining Allosterism in a Dimeric G-Protein-Coupled

5.1 G-Protein-Coupled Receptors: Paradigms of

Chapter 6 A Unifying Approach to the Duality of “Energetic” Versus

6.1 Introduction  131

7.1 Introduction  156

7.2 mGlu2 Receptor Positive Allosteric Modulators  157

Chapter 8 Muscarinic Receptors Allosteric Modulation  175

8.1 Introduction  175

Chapter 9 Positive Allosteric Modulators of Opioid Receptors  194

9.1 Opioid Receptors and Pain  194

Chapter 10 mGlu4 PET Ligands as Enablers of Target Biology

10.1 Introduction  220

Chapter 11 Allosteric Modulators of Adenosine, P2Y and P2X

11.1 Introduction  247

11.3.1 NAMs of the P2Y1R  256

Chapter 12 Positive Allosteric Modulators of G-Protein-Coupled

12.1 Introduction  271

Chapter 13 Mechanism of Action of a GluN2C- and GluN2D-Selective

13.1 Introduction  281

13.6.2 CIQ as a Pharmacological Probe for

Chapter 14 Development of AMPA Receptor Modulators as

14.1 Introduction  310

Chapter 15 Allosteric Modulation of Neuronal Nicotinic

1.1 Drug Discovery in the Early 21st Century 1

Chapter 2 Identifying and Quantifying Allosteric Drug Function 24

2.1 Introduction: Receptor Allosterism 24

Chapter 3 Targeting Catalytic and Non-Catalytic Functions of

Chapter 4 Molecular Biology Techniques Applied to GPCR Allosteric

Chapter 5 Examining Allosterism in a Dimeric G-Protein-Coupled

5.1 G-Protein-Coupled Receptors: Paradigms of

Chapter 6 A Unifying Approach to the Duality of “Energetic” Versus

6.1 Introduction 131

7.1 Introduction 156

7.2 mGlu2 Receptor Positive Allosteric Modulators 157

Chapter 8 Muscarinic Receptors Allosteric Modulation 175

8.1 Introduction 175

Chapter 9 Positive Allosteric Modulators of Opioid Receptors 194

9.1 Opioid Receptors and Pain 194

Chapter 10 mGlu4 PET Ligands as Enablers of Target Biology

10.1 Introduction 220

Chapter 11 Allosteric Modulators of Adenosine, P2Y and P2X

11.1 Introduction 247

11.3.1 NAMs of the P2Y1R 256

Chapter 12 Positive Allosteric Modulators of G-Protein-Coupled

12.1 Introduction 271

Chapter 13 Mechanism of Action of a GluN2C- and GluN2D-Selective

13.1 Introduction 281

13.6.2 CIQ as a Pharmacological Probe for

Chapter 14 Development of AMPA Receptor Modulators as

14.1 Introduction 310

Chapter 15 Allosteric Modulation of Neuronal Nicotinic

15.1 Introduction 334

16.1 Introduction 360

Chapter 17 Allosteric Inhibition of Abl Kinase 381

17.1 Introduction 381

Chapter 18 Allosteric Modulators of Heat Shock Protein 90 (HSP90) 404

18.1 Introduction: Molecular Chaperones 404

Subject Index 427

1.1 Drug Discovery in the Early 21st Century

1.2 Allostery: A 50-Year Old Concept

1.3 llosteric Drugs: The Right Tool at the Right

1.4 otential Advantages of Allosteric Modulators

1.5 Looking Under the Hood