Chapter 2. WCU
Chapter 2. WCU
Chapter 2. WCU
By Melkamu.A
6/3/2022 By Melkamu.A 1
Overview of Nervous System
6/3/2022 By Melkamu.A 2
6/3/2022 By Melkamu.A 3
Motor nerves
Without motor nerves:
No breathing.
Digestion.
Excretion.
Muscle movement.
Control of body temperature.
Heart problems.
6/3/2022 By Melkamu.A 4
Motor nerves
1. Somatic motor NS:
carry messages from CNS to the skeletal muscles.
Acetylcholine is the neurotransmitter.
6/3/2022 By Melkamu.A 5
Cont’d…
2. Autonomic motor NS:
Carry messages from the CNS to smooth muscle,
cardiac muscle and adrenal medulla.
Two subsystems:
I. 1. Parasympathetic nerves:
From CNS to smooth muscles.
Acetylcholine is the N.T.
II. 2. Sympathetic nerves:
To the cardiac muscles and most of internal organs.
Using Noradrenalin and Acetylcholine as N.T
6/3/2022 By Melkamu.A 6
Cont’d…
Autonomic nervous system (ANS)
Acts on smooth muscles & glands
Controls and regulates the heart, respiratory system, GI tract, bladder, eyes and
salivary glands, etc .
6/3/2022 By Melkamu.A 7
Adrenaline action
Fight or Flight
6/3/2022 By Melkamu.A 8
Cont’d…
3. Enteric NS:
– Located in the wall of intestine.
– Use serotonin, neuropeptide, Acetylcholine and Dopamine are among
many other neurotransmitters take part in this system
6/3/2022 By Melkamu.A 9
Cont’d…
6/3/2022 By Melkamu.A 10
Cont’d…
6/3/2022 By Melkamu.A 11
Cont’d…
6/3/2022 By Melkamu.A 12
SAR for acetylcholine
O O
CMe3 NMe2
H3C O H3C O
O O
H 3C O H 3C O
NMe3 NMe3
Ester is important
NMe3 NMe3
H 3C O H 3C
6/3/2022 By Melkamu.A 15
Cont’d…
O Et
O Et
N Me
N Et H 3C O
H 3C O Me
Et
6/3/2022 By Melkamu.A 16
Cont’d…
H 3C
NMe3
O
Conclusions:
• Tight fit between Ach and binding site
• Methyl groups fit into small hydrophobic pockets
• Ester interacting by H-bonding
• Quaternary nitrogen interacting by ionic bonding
6/3/2022 By Melkamu.A 18
Binding site (muscarinic)
hydrophobic
pocket Trp-307
Asp311
CH3 CH3
CO2
N CH3
hydrophobic
O O
pockets
CH3
Trp-616 Trp-613
H
H
O N hydrophobic
pocket
Asn-617
6/3/2022 By Melkamu.A 19
Cont’d…
vdw Trp-307
Asp311
CH3 CH3
CO2
Ionic bond
N CH3 vdw
O O
H-bonds CH3 vdw
Trp-616 Trp-613
H
H
O N
Asn-617
6/3/2022 By Melkamu.A 20
Cholinergic Agents
Direct acting - act on the receptors to activate a tissue response
Indirect acting - inhibit the action of the enzyme
Acetylcholinesterase:
6/3/2022 By Melkamu.A 21
Cont’d…
6/3/2022 By Melkamu.A 22
Hydrolysis of Acetylcholine
6/3/2022 By Melkamu.A 23
Acetylcholine (Ach)
Acetyl Choline
6/3/2022 By Melkamu.A 24
Cholinergic receptors
1. Muscarinic receptors:
Found in smooth muscles and cardiac muscles.
Related to muscarine.
2. Nicotinic receptors:
Found in skeletal muscles.
Related to nicotine.
6/3/2022 By Melkamu.A 25
Subtypes of M1 M2 M3 M4 M5
M- receptor Neural Cardiac Glandular,
smooth muscles
Main CNS, Gastric & Heart , GIT, Gastric & CNS CNS
location salivary glands CNS salivary glands,
GIT, Eye
Cellular Increase IP3, Decrease in Increase IP3, As M2 As M3
response DAG, a) cAMP Ca++
Depolarization, inhibition, conductance,
excitation, b) Ca++
increase conductance,
potassium
conductance Increase K+
conductance
Functional CNS excitation, Cardiac Gastric & saliva Enhanced Not
responses gastric secretion inhibition, secretion, GI locomotion
known
neural smooth muscle
inhibition contraction,
occular
accomodation
6/3/2022 By Melkamu.A 26
Cholinergic agonists
Acetylcholine as an agonist
Advantages
• Natural messenger
• Easily synthesised
Disadvantages
• Easily hydrolysed in stomach (acid catalysed hydrolysis)
• Easily hydrolysed in blood (esterases)
• No selectivity between receptor types
• No selectivity between different target organs
6/3/2022 By Melkamu.A 27
L-serine ethanolamine
choline Acetylcholine
6/3/2022 By Melkamu.A 28
Biological hydrolysis of Ach
6/3/2022 By Melkamu.A 29
Cholinergic agonists
Advantages
Disadvantages
• Activate receptors for other chemical messengers
• Side effects
6/3/2022 By Melkamu.A 30
6/3/2022 By Melkamu.A 31
Requirements for cholinergic agonists
6/3/2022 By Melkamu.A 32
Uses of cholinergic agonists
6/3/2022 By Melkamu.A 33
Design of cholinergic agonists
6/3/2022 By Melkamu.A 34
Acetylcholine analogues
To overcome the instability of Ach:
Steric shield: add large group to change the conformation of Ach:
6/3/2022 By Melkamu.A 35
Acetylcholine analogues
6/3/2022 By Melkamu.A 36
Acetylcholine analogues
More stable.
More selective on muscarinic receptor.
Used to stimulate GIT and urinary bladder after
surgery.
6/3/2022 By Melkamu.A 37
Muscarinic agonists
Clinical uses:
Treatment of glaucoma.
Stimulate GIT and UT after surgery.
In some heart defects.
Pilocarpine:
6/3/2022 By Melkamu.A 38
Cont’d…
Oxotremorine and Arecoline:
6/3/2022 By Melkamu.A 39
Nicotinic agonists
•
Clinical use:
Varenicline is indicated for smoking cessation, as an alternative to bupropion
and nicotine patches.
Time of treatment, with a maintenance dose of 1 mg twice daily, is 12 weeks.
6/3/2022 By Melkamu.A 40
Acetylcholinesterase Inhibitors (AChEIs)
6/3/2022 By Melkamu.A 41
Cont’d…
Reversible AChEIs are composed of:
Substrates for AChE which acylate the enzyme followed by deacylation.
Most of these agents are carbamates, not esters, and form carbamylated
AChE and are more resistant to hydrolysis.
Substrates with greater binding affinity for AChE than ACh, but do not
acetylate the enzyme.
Irreversible AChEIs (echothiophate iodide) are: commonly phosphate
esters, which phosphorylate AChE and only slowly dephosphorylate
and, as a result, have high potential toxicity.
6/3/2022 By Melkamu.A 42
Cont’d…
Echothiophate iodide is indicated for treatment of open-angle
glaucoma
Edrophonium chloride is recommended for diagnosis of myasthenia
gravis, but its short duration of action is a limiting factor for its use.
On the other hand, neostigmine methylsulfate and pyridostigmine
bromide are used to control myasthenia gravis, with the former being
administered SC or IM while the latter is effective orally
The four remaining drugs rivastigmine tartrate, donepezil and tacrine
hydrochloride, and galantamine hydrobromide have been approved for
treatment of mild to moderate dementia including Alzheimer’s type.
6/3/2022 By Melkamu.A 43
Cont’d…
Organophosphate insecticides irreversible AChEIs with varying
degrees of human toxicity
6/3/2022 By Melkamu.A 44
Cholinergic Antagonists
Of two types:
Muscarinic antagonists:
The prototype drug here is Atropine
6/3/2022 By Melkamu.A 45
SAR of cholinergic antagonists
6/3/2022 By Melkamu.A 47
Based on this definition
The chemical structure of receptor antagonist does not
necessarily mimic the natural ligand structure;
Antagonist is generally bulkier, having extra
binding groups compared to the natural ligand
Clinical Effects
Uses
• Shutting down digestion for surgery
• Ophthalmic examinations
• Relief of peptic ulcers
• Treatment of Parkinson’s Disease
• Anticholinesterase poisoning
• Motion sickness
• Treatment of overactive bladder.
The anticholinergics tiotropium, ipratropium, aclidinium, and umeclidinium are used for the
long-term maintenance treatment of bronchospasms (long-acting muscarinic antagonists)
(LAMAs) seen in chronic obstructive pulmonary disease (COPD) as well as chronic bronchitis.
Scopolamine, in the form of a transdermal patch, is used for the prevention of motion sickness
Cholinergic Antagonists
Nicotinic antagonists:
The nicotine antagonists fall into two subclasses – the ganglionic blocking
agents and the NM blocking agents
The prototype drug is tubocurarine
MeO
Me
N
HO Me
H CH2
O
CH2
H
Me
O
H N OH
OMe
6/3/2022 By Melkamu.A 52
Cont’d…
Clinical uses:
NM blocking agents are used primarily as an adjunct to general anesthesia.
They produce skeletal muscle relaxation that facilitates operative procedures such as abdominal
surgery and reduce the depth requirement for general anesthetics, thus decreasing the overall risk
of a surgical procedure and shortens the postanesthetic recovery time.
6/3/2022 By Melkamu.A 53
Adrenergic Agents
The term adrenergic comes from the word “adrenaline,” a synonym for
epinephrine (Epi), the N-methylated analog of the neurotransmitter
norepinephrine (NE).
Endogenous Adrenergics:
NE is the adrenergic neurotransmitter produced and released from presynaptic terminals
Epi, a neurohormone, is produced in and secreted by the adrenal medulla.
The precursor of both endogenous adrenergics is L-tyrosine.
6/3/2022 By Melkamu.A 54
Cont’d…
Note that stimulation of sympathetic nervous system uses what is
known as “Fight or flight” response .
These effects include:
Increased rate and force of heart contraction
Increased blood pressure
Increased blood flow to brain, heart and skeletal muscles
Increase in blood glucose levels (through gluconeogenesis and glycogenolysis) for energy
Pupil and bronchiole dilation
Stimulants such as Epinephrine does this by its effects on alpha and
beta receptors that are found in many animals
6/3/2022 By Melkamu.A 55
Cont’d…
6/3/2022 By Melkamu.A 56
Biosynthesis of epinephrine and NE
6/3/2022 By Melkamu.A 57
Direct adrenergic drug action (Adrenergic agonists)
Excellent for cardiac stimulant and vasoconstrictive effects in cardiac arrest, and also
added to local anesthetic to be used for treatment of Anaphylaxis, and glaucoma
Serious side effects include cerebral hemorrhage and cardiac arrhythmias
6/3/2022 By Melkamu.A 58
Cont’d…
2. Isuprel (isoproterenol)
It is a synthetic drug and a direct acting adrenergic receptor agonists or β-
receptor agonists (or it binds to both β-1 and β-2 receptors without selectivity)
Stimulates heart, dilates blood vessels in skeletal muscle and causes
bronchodilation.
No alpha stimulation or has low affinity to α-receptors.
6/3/2022 By Melkamu.A 59
Cont’d…
6/3/2022 By Melkamu.A 60
Cont’d…
4. Dopamine (Intropin)
Direct acting adrenergic receptor agonists: β1 receptors.
5. Clonidine
Direct acting adrenergic receptor agonists: selective α2 receptors.
6/3/2022 By Melkamu.A 61
Cont’d…
SAR of the phenylethylamine and arylimidazoline adrenergic agonist.
6/3/2022 By Melkamu.A 62
Indirect adrenergic drug action
Occurs by stimulation of postsynaptic α-1, β1 and β2 receptors.
Cause release of endogenous norepinephrine (NE) (naturally occurring
hormone) from the adrenergic nerve terminals into the synapse of
nerve endings which then stimulates the receptor.
Act by blocking and reversing norepinephrine transporter (NET)
activity
Some examples of indirect acting drugs are amphetamine,
pseudoephedrine, ephedrine, phenylpropanolamine, tyramine, Tricyclic
antidepressants (TCAs)
6/3/2022 By Melkamu.A 63
Cont’d…
6/3/2022 By Melkamu.A 64
Cont’d…
6/3/2022 By Melkamu.A 65
Cont’d…
6/3/2022 By Melkamu.A 66
Cont’d…
6/3/2022 By Melkamu.A 67
Cont’d…
6/3/2022 By Melkamu.A 68
Antiadrenergic drugs/Sympatholytic agents/
Adrenergic blocking drugs
Block or decrease the effects of sympathetic nerve stimulation, endogenous
catecholamines and adrenergic drugs.
6/3/2022 By Melkamu.A 69
Cont’d…
6/3/2022 By Melkamu.A 70
Cont’d…
Structure of some commercial α-blockers
6/3/2022 By Melkamu.A 71
Cont’d…
6/3/2022 By Melkamu.A 72
Cont’d…
6/3/2022 By Melkamu.A 73
Cont’d…
6/3/2022 By Melkamu.A 74
Cont’d…
6/3/2022 By Melkamu.A 75