Papers by Maria Isabel Cadavid
Journal of medicinal chemistry, Jan 3, 2017
A novel family of structurally simple, potent and selective non-xanthine A2BAR ligands was identi... more A novel family of structurally simple, potent and selective non-xanthine A2BAR ligands was identified and its antagonistic behavior was confirmed through functional experiments. The reported alkyl 2-cyanoimino-4-substituted-6-methyl-1,2,3,4-tetrahy-dropyrimidine-5-carboxylates (16) were designed by bioisosteric replacement of the carbonyl group at position 2 in a series of 3,4-dihydropyrimidin-2-ones. The scaffold (16) documented herein contains a chiral center at the heterocycle. Accordingly, the most attractive ligand of the series [(±)16b, Ki = 24.3 nM] was resolved into its two enantiomers by chiral HPLC and the absolute configuration was established by circular dichroism. The biological evaluation of both enantiomers demonstrated enantiospecific recognition at A2BAR, with the (S)-16b enantiomer retaining all the affinity (Ki = 15.1 nM), as predicted earlier by molecular modeling. This constitutes the first example of enantiospecific recognition at the A2B adenosine receptor and...
Journal of biomolecular screening, Jan 19, 2016
G protein-coupled receptors (GPCRs) exist as collections of conformations in equilibrium, and the... more G protein-coupled receptors (GPCRs) exist as collections of conformations in equilibrium, and the efficacy of drugs has been proposed to be associated with their absolute and relative affinities for these different conformations. The serotonin 2A(5-HT2A) receptor regulates multiple physiological functions, is involved in the pathophysiology of schizophrenia, and serves as an important target of atypical antipsychotic drugs. This receptor was one of the first GPCRs for which the functional selectivity phenomenon was observed, with its various ligands exerting differential effects on the phospholipase A2(PLA2) and phospholipase C (PLC) signaling pathways. We aimed to develop a multiplex functional assay in 96-well plates for the simultaneous measurement of the PLA2and PLC pathways coupled to 5-HT2Areceptors; this approach enables the detection of either functional selectivity or cooperativity phenomena in early drug screening stages. The suitability of the method for running screening...
5-HT7 receptors are the last identified members of the serotonin receptor family. The development... more 5-HT7 receptors are the last identified members of the serotonin receptor family. The development of 5-HT7 receptor ligands has important implications for CNS pharmacology and therapy. We performed a detailed in vitro pharmacological characterization of two arylpiperazine derivatives, compound LP-211 previously identified as a high affinity brain penetrant ligand for 5-HT7 receptors, and its analog MEL-9. Both ligands exhibited competitive displacement of [3H]-SB-269970 radioligand binding and insurmountable antagonism of 5-CT-stimulated cAMP signaling in HEK293 cells stably expressing human 5-HT7 receptors. Like 5-HT7 antagonists, the compounds inhibited forskolinstimulated adenylate cyclase activity in 5-HT7-expressing HEK293 cells but not the parental cell line. The compounds elicited longlasting (at least 24 h) concentration-dependent inactivation of 5-HT7 binding sites in whole cell radioligand binding assays, after pretreatment of the cells with the compounds and subsequent re...
General Pharmacology: The Vascular System, 2000
In this work, we report for first time that: (1) low doses of ketanserin (0.2 mg/kg) produce a tr... more In this work, we report for first time that: (1) low doses of ketanserin (0.2 mg/kg) produce a transient hypotensive response in anaesthetized rats, which is basically due to the blockade of 5-hydroxytryptamine 2A (5-HT) 2A receptors, whereas high doses (1 mg/kg) of ketanserin cause a sustained hypotension also mediated by the blockage of a 1-adrenergic receptors; (2) the in vitro vasorelaxant action of high concentrations of ketanserin (> 10 mM) involves Ca 2 + antagonism, which may also be responsible, at least in part, for the inhibition of high-K +-induced 45 Ca 2 + uptake, the inhibition of Ca 2 +-induced contractions in initially Ca 2 +-free high-K + medium, and the negative chronotropic effects on isolated atria. This Ca 2+ antagonistic activity does not seem to contribute to the in vivo cardiovascular effects of ketanserin at therapeutic doses.
Neuropharmacology, 2006
Patterns of protein expression can be used to identify biomarkers of disease, prognosis or treatm... more Patterns of protein expression can be used to identify biomarkers of disease, prognosis or treatment response. Peripheral 5-HT2A and D3 receptors have been proposed as protein markers in schizophrenia. We investigated the possible parallel regulation of these candidate biomarkers in central nervous system (CNS) and peripheral blood cells by a comparative study of the effects of antipsychotic treatment on the expression of the receptors in both systems in rats. Acute (24 and 48 h) and subchronic (16 days) treatment of rats with olanzapine induced a significant decrease in 5-HT2A receptor density both in frontal cortex (Bmax=76.2%, 83.0% and 46.0% of control after 24 h, 48 h and 16 days of treatment, respectively; P<0.01) and blood platelets (Bmax approximately 55% of control at all times measured; P<0.01), without any changes in receptor affinity. Furthermore, olanzapine induced redistribution in 5-HT2A-like immunoreactivity and time-dependent remodelling of synaptic circuits involved in the activity of pyramidal and GABAergic neurons in frontoparietal motor cortex of treated rats, as assessed by immunohistochemical studies. D3 receptor mRNA levels increased significantly by 52.5%…
ACS Chemical Neuroscience, 2012
A neural network model has been developed to predict the inhibitory capacity of any chemical stru... more A neural network model has been developed to predict the inhibitory capacity of any chemical structure to be a phosphodiesterase 7 (PDE7) inhibitor, a new promising kind of drugs for the treatment of neurological disorders. The numerical definition of the structures was achieved using CODES program. Through the validation of this neural network model, a novel family of 5-imino-1,2,4-thiadiazoles (ITDZs) has been identified as inhibitors of PDE7. Experimental extensive biological studies have demonstrated the ability of ITDZs to inhibit PDE7 and to increase intracellular levels of cAMP. Among them, the derivative 15 showed a high in vitro potency with desirable pharmacokinetic profile (safe genotoxicity and blood brain barrier penetration). Administration of ITDZ 15 in an experimental autoimmune encephalomyelitis (EAE) mouse model results in a significant attenuation of clinical symptoms, showing the potential of ITDZs, especially compound 15, for the effective treatment of multiple sclerosis.
Journal of Medicinal Chemistry, 2014
Naunyn-Schmiedeberg's Archives of Pharmacology, 2003
Most studies of 5-HT 2 receptor regulation have been carried out on the central nervous system (C... more Most studies of 5-HT 2 receptor regulation have been carried out on the central nervous system (CNS) (which expresses 5-HT 2A and 5-HT 2C receptors); very few in vitro studies have addressed the peripheral receptors 5-HT 2A and 5-HT 2B. The aim of this investigation was to compare the possible short-and long-term processes regulating these peripheral receptors in the rat. The in vitro contractile response elicited by serotonin (5-HT, 10 µM) in the rat gastric fundus (5-HT 2B receptor system) was rapid and followed by a partial fade to a steady state, in contrast with the rat thoracic aorta response (5-HT 2A receptor system), which was more stable, slower and sustained. To characterize drug-receptor interactions, cumulative concentration/response curves (CCRCs) for 5-HT were constructed ex vivo for rat tissues treated with drugs acting at these receptors. Rats were examined 4 or 24 h after a single, i.p. administration of (±)1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane [(±)DOI, 1 or 2.5 mg/ kg], clozapine, cyproheptadine or rauwolscine (10 mg/kg), 48 h after a single i.p. administration of (±)DOI (2.5 mg/ kg), clozapine or cyproheptadine (10 mg/kg) or 24 h after the last of with 15 daily i.p. administrations of (±)DOI (1 or 2.5 mg/kg), clozapine, cyproheptadine or rauwolscine (10 mg/kg). In the aorta, E max (the maximum response elicited by 5-HT) was unchanged 4 h after a single dose of any of the drugs tested. However, 24 h after a single dose, E max was lower in animals treated with (±)DOI (2.5 mg/ kg), clozapine or cyproheptadine than in controls, whilst 48 h after a single dose of (±)DOI (2.5 mg/kg), clozapine or cyproheptadine there was no difference in E max between experimental and control animals. After chronic treatment with (±)DOI (2.5 mg/kg), clozapine and cyproheptadine, E max was lower than in controls. In the gastric fundus, E max 4 h after a single dose of each drug was lower than in controls, and the response recovered by 24 or 48 h. Following chronic treatment, E max was significantly lower than in controls for each drug used. These findings suggest first, that regulation of peripheral 5-HT 2 receptors (5-HT 2A and 5-HT 2B) is a functionally significant phenomenon in vivo, and occurs after administration of both agonists and antagonists. Second, the kinetics of peripheral 5-HT 2 receptor regulation were similar in both in vivo and ex vivo experiments. The 5-HT 2B receptors in rat gastric fundus are more sensitive to druginduced regulation than the 5-HT 2A rat aortic receptors. Finally, long-term regulation of both receptors stabilizes short-term desensitization for longer. Keywords (±)DOI • Clozapine • Cyproheptadine • Rauwolscine • Rat thoracic aorta • Rat gastric fundus • 5-HT 2A receptor • 5-HT 2B receptor • Ex vivo treatments
Molecular Pharmacology, 2009
The serotonin (5-hydroxytryptamine; 5-HT) 2A receptor is a cell surface class A G protein-coupled... more The serotonin (5-hydroxytryptamine; 5-HT) 2A receptor is a cell surface class A G protein-coupled receptor that regulates a multitude of physiological functions of the body and is a target for antipsychotic drugs. Here we found by means of fluorescence resonance energy transfer and immunoprecipitation studies that the 5-HT 2A-receptor homodimerized in live cells, which we linked with its antagonist-dependent fingerprint in both binding and receptor signaling. Some antagonists, like the atypical antipsychotics clozapine and risperidone, differentiate themselves from others, like the typical antipsychotic haloperidol, antagonizing these 5-HT 2A receptor-mediated functions in a pathway-specific manner, explained here by a new model of multiple active interconvertible conformations at dimeric receptors.
QSAR & Combinatorial Science, 2009
... Hugo Gutiérrez-de-Terán,a Carla Correia,c David Rodríguez,a Maria Alice Carvalho,c Jose Brea,... more ... Hugo Gutiérrez-de-Terán,a Carla Correia,c David Rodríguez,a Maria Alice Carvalho,c Jose Brea,b María Isabel Cadavid,b María Isabel Loza,b Maria Fernanda ProenÅa,c Filipe Areiasb, c* a Fundación Pública Galega de Medicina ... [9] T. Warne, MJ Serrano-Vega, JG Baker, R ...
Journal of Medicinal Chemistry, 2002
Journal of Medicinal Chemistry, 2007
A novel series of N-heteroaryl 4′-(2-furyl)-4,5′-bipyrimidin-2′-amines has been identified as pot... more A novel series of N-heteroaryl 4′-(2-furyl)-4,5′-bipyrimidin-2′-amines has been identified as potent and selective A 2B adenosine receptor antagonists. In particular, compound 5 showed high affinity for the A 2B receptor (K i) 17 nM), good selectivity (IC 50 : A 1 > 1000 nM, A 2A > 2500 nM, A 3 > 1000 nM), displayed a favorable pharmacokinetic profile in preclinical species, and showed efficacy in functional in vitro models.
Journal of Medicinal Chemistry, 2012
Phosphodiesterase (PDE) 7 is involved in pro-inflammatory processes being widely expressed both o... more Phosphodiesterase (PDE) 7 is involved in pro-inflammatory processes being widely expressed both on lymphocytes and on certain brain regions. Specific inhibitors of PDE7 have been recently reported as potential new drugs for the treatment of neurological disorders due to their ability to increase intracellular levels of cAMP and thus, modulating the inflammatory process, as a neuroprotective well-established strategy. Multiple sclerosis is an unmet disease in which pathologies on inmunitary system, T-cells, and specific neural cells are involved simultaneously. Therefore, PDE7 inhibitors able to interfere with all these targets may represent an innovative therapy for this pathology. Here, we report a new chemically diverse family of heterocyclic PDE7 inhibitors, discovered and optimized by using molecular modeling studies, able to increase cAMP levels in cells, decrease inflammatory activation on primary neural cultures and also attenuate the clinical symptoms in the experimental autoimmune encephalomyelitis (EAE) mouse model. These results led us to propose the use of PDE7 inhibitors as innovative therapeutic agents for the treatment of multiple sclerosis.
Journal of Medicinal Chemistry, 2011
European Journal of Medicinal Chemistry, 2013
European Journal of Medicinal Chemistry, 2003
A series of novel conformationally restricted butyrophenones (6-aminomethyl-4,5,6,7-tetrahydroben... more A series of novel conformationally restricted butyrophenones (6-aminomethyl-4,5,6,7-tetrahydrobenzo[b]furan-4-ones bearing 4-(6-fluorobenzisoxazolyl)piperidine, 4-(p-fluorobenzoyl)piperidine, 4-(o-methoxyphenyl)piperazine, 4-(2-pyridyl)piperazine, 4-(2-pyrimidinyl)piperazine, or linear butyro(or valero)phenone fragments) were prepared and evaluated as antipsychotic agents by in vitro assays for affinity for dopamine receptors (D 1 , D 2 , D 4) and serotonin receptors (5-HT 2A , 5-HT 2B , 5-HT 2C), by neurochemical studies, and by in vivo assays for antipsychotic potential and the risk of inducing extrapyramidal side effects. Potency and selectivity depended mainly on the amine fragment connected to the cyclohexanone structure. Compounds 20b, with a benzoylpiperidine moiety, and 20c, with a benzisoxazolyl fragment, were selective for 5-HT 2A receptors. The in vitro and in vivo pharmacological profiles of N-[(4-oxo-4,5,6,7-tetrahydrobenzo-[b]furan-6-yl)methyl]-4-(p-fluorobenzoyl)piperidine (20b, QF1003B) and N-[(4-oxo-4,5,6,7-tetrahydrobenzo[b]furan-6-yl)methyl]-4-(6-fluorobenzisoxazol-3-yl)piperidine (20c, QF1004B) suggest that they may be effective as antipsychotic (neuroleptic) drugs. § This is the 22nd paper in the series "Synthesis and CNS Activity of Conformationally Restricted Butyrophenones"; for preceding papers, see ref 47.
European Journal of Medicinal Chemistry, 2013
Novel analogs of L-prolyl-L-leucylglycinamide (PLG) were synthesized wherein the prolyl residue w... more Novel analogs of L-prolyl-L-leucylglycinamide (PLG) were synthesized wherein the prolyl residue was replaced with other amino acids based on a 3,5-disubstituted proline scaffold. In some examples, the Lleucyl residue was also replaced by L-valine. These analogs were tested for their ability to enhance the binding of [ 3 H]-N-propylnorapomorphine to short isoform of human dopamine D 2 receptors. Compounds 18b and 19b, increased [ 3 H] NPA binding at concentrations between 10 À12 and 10 À9 M, which is similar to the effect of PLG in this assay and, provides evidences that these compounds are acting as allosteric modulators of dopamine D 2 receptors.
European Journal of Medicinal Chemistry, 2012
European Journal of Medicinal Chemistry, 2004
A number of 8-substituted-9-deazaxanthine derivatives (1,3-dialkyl-6-substituted-1H-pyrrolo[3,2-d... more A number of 8-substituted-9-deazaxanthine derivatives (1,3-dialkyl-6-substituted-1H-pyrrolo[3,2-d]pyrimidine-2,4(3H,5H)-diones) were prepared and tested for their antagonistic activity at the recombinant human adenosine receptors, in particular at the A 2B and A 2A receptor subtypes. Compounds endowed with micromolar to nanomolar binding affinities, but with poor A 2B /A 2A selectivity, were obtained. Preliminary quantitative structure-affinity relationships suggested that the binding potency at the A 2B receptor is mainly modulated by the electronic and lipophilic properties of the ligands.
Chemical and Pharmaceutical Bulletin, 1997
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Papers by Maria Isabel Cadavid