ABSTRACT
The 5-hydroxytryptamine 2C (5-HT(2C)) receptor subtype has received considerable attention as a target for drug discovery, having been implicated in a wide variety of disorders. Here, we describe the in vitro pharmacological profile of the novel 5-HT(2C) receptor-selective agonist vabicaserin [(-)-4,5,6,7,9,9a,10,11,12,12a-decahydrocyclopenta[c] [1,4]diazepino[6,7,1-ij]quinoline hydrochloride] (SCA-136), including a comprehensive strategy to assess 5-HT(2B) receptor selectivity using diverse preparations and assays of receptor activation. Vabicaserin displaced (125)I-(2,5-dimethoxy)phenylisopropylamine binding from human 5-HT(2C) receptor sites in Chinese hamster ovary cell membranes with a K(i) value of 3 nM and was >50-fold selective over a number of serotonergic, noradrenergic, and dopaminergic receptors. Binding affinity determined for the human 5-HT(2B) receptor subtype using [(3)H]5HT was 14 nM. Vabicaserin was a potent and full agonist (EC(50), 8 nM; E(max), 100%) in stimulating 5-HT(2C) receptor-coupled calcium mobilization and exhibited 5-HT(2A) receptor antagonism and 5-HT(2B) antagonist or partial agonist activity in transfected cells, depending on the level of receptor expression. In rat stomach fundus and human colonic longitudinal muscle endogenously expressing 5-HT(2B) receptors, vabicaserin failed to induce a 5-HT(2B) receptor-dependent contraction and produced a rightward shift of the 5-HT and α-methyl-5-HT concentration-response curves in these preparations, respectively, consistent with 5-HT(2B) competitive antagonism. Likewise, vabicaserin failed to induce a 5-HT(2B) receptor-mediated contraction in arteries from deoxycorticosterone acetate-salt-treated rats, a model of hypersensitized 5-HT(2B) receptor function, and produced a rightward shift in the 5-HT-induced response that was consistent with 5-HT(2B) receptor antagonism. In summary, vabicaserin is a novel, potent, and selective 5-HT(2C) receptor agonist.
Subject(s)
Antipsychotic Agents/metabolism , Antipsychotic Agents/pharmacology , Heterocyclic Compounds, 4 or More Rings/metabolism , Heterocyclic Compounds, 4 or More Rings/pharmacology , Receptor, Serotonin, 5-HT2C/metabolism , Serotonin 5-HT2 Receptor Agonists/metabolism , Serotonin 5-HT2 Receptor Agonists/pharmacology , Animals , Binding Sites/drug effects , CHO Cells , Cell Line , Cricetinae , Cricetulus , Humans , Male , Molecular Targeted Therapy , Muscle Contraction/drug effects , Muscle, Smooth/drug effects , Muscle, Smooth/physiology , Protein Binding/drug effects , Rats , Rats, Sprague-Dawley , Receptor, Serotonin, 5-HT2A/metabolism , Receptor, Serotonin, 5-HT2B/metabolism , Recombinant Proteins/metabolism , Serotonin/analogs & derivatives , Serotonin/metabolism , Serotonin 5-HT2 Receptor Antagonists/metabolism , Serotonin 5-HT2 Receptor Antagonists/pharmacology , Signal Transduction/drug effectsABSTRACT
1-(2-Aminoethyl)-3-(arylsulfonyl)-1H-pyrrolopyridines were prepared. Binding assays indicated they are 5-HT(6) receptor ligands, among which 6f and 6g showed high affinity for 5-HT(6) receptors with K(i)=3.9 and 1.7 nM, respectively.
Subject(s)
Pyridines/pharmacology , Pyrroles/pharmacology , Receptors, Serotonin/drug effects , Serotonin Antagonists/pharmacology , Serotonin Receptor Agonists/pharmacology , HeLa Cells , Humans , Ligands , Pyridines/chemistry , Pyrroles/chemistry , Receptors, Serotonin/metabolism , Serotonin Antagonists/chemistry , Serotonin Receptor Agonists/chemistryABSTRACT
A series of 1-aminoethyl-3-arylsulfonyl-1H-pyrrolo[2,3-b]pyridines 10a-z was prepared as novel 5-HT(6) ligands. The best compounds were high affinity, full agonists at 5-HT(6) receptors. Several agonists demonstrated good selectivity over other serotonergic and dopaminergic receptors. Acute administration of selective agonist 10e significantly increased extracellular GABA concentrations in rat frontal cortex. This compound also reduced adjunctive drinking behavior in the rat schedule-induced polydipsia assay, possibly predictive of efficacy in obsessive compulsive disorder and other anxiety related disorders.
Subject(s)
Cerebral Cortex/drug effects , Drinking Behavior/drug effects , Receptors, Serotonin/metabolism , Serotonin Receptor Agonists/chemistry , Serotonin Receptor Agonists/pharmacology , Animals , Cerebral Cortex/metabolism , Glutamic Acid/analysis , Glutamic Acid/metabolism , HeLa Cells , Humans , Protein Binding , Rats , Serotonin Receptor Agonists/administration & dosage , Serotonin Receptor Agonists/chemical synthesis , gamma-Aminobutyric Acid/analysis , gamma-Aminobutyric Acid/metabolismABSTRACT
N1-Arylsulfonyltryptamines have been identified as 5-HT6 receptor ligands. In particular, N1-(6-chloroimidazo[2,1-b][1,3]thiazole-5-sulfonyl)tryptamine (11q) is a high affinity, potent full agonist (5-HT6 Ki = 2 nM, EC50 = 6.5 nM, Emax = 95.5%). Compound 11q is selective in a panel of over 40 receptors and ion channels, has good pharmacokinetic profile, has been shown to increase GABA levels in the rat frontal cortex, and is active in the schedule-induced polydipsia model for obsessive compulsive disorders.
Subject(s)
Receptors, Serotonin/metabolism , Serotonin Receptor Agonists/chemical synthesis , Thiazoles/chemistry , Tryptamines/chemical synthesis , Administration, Oral , Animals , Biological Availability , CHO Cells , Cricetinae , Cricetulus , Dogs , Frontal Lobe/metabolism , Haplorhini , Humans , In Vitro Techniques , Mice , Microdialysis , Microsomes, Liver/metabolism , Radioligand Assay , Rats , Serotonin Receptor Agonists/pharmacokinetics , Serotonin Receptor Agonists/pharmacology , Solubility , Structure-Activity Relationship , Thiazoles/pharmacokinetics , Thiazoles/pharmacology , Tryptamines/chemistry , Tryptamines/pharmacokinetics , Tryptamines/pharmacology , gamma-Aminobutyric Acid/metabolismABSTRACT
Synthesis and structure-activity relationships (SAR) of arginine vasopressin (AVP) receptor modulators are described. Potent and selective compounds are prepared when the amide linkage connecting rings A and B of VPA-985 is replaced with a bond, CO, -O-, -S-, or -SO2- bond.
Subject(s)
Benzodiazepines/chemical synthesis , Benzodiazepines/pharmacology , Pyrroles/chemical synthesis , Pyrroles/pharmacology , Receptors, Vasopressin/metabolism , Antidiuretic Hormone Receptor Antagonists , Benzodiazepines/chemistry , Blood Platelets/drug effects , Blood Platelets/metabolism , Humans , Inhibitory Concentration 50 , Molecular Structure , Pyrroles/chemistry , Sensitivity and Specificity , Structure-Activity RelationshipABSTRACT
5-Arylsulfonylamido-3-(pyrrolidin-2-ylmethyl)-1H-indoles have been identified as high-affinity 5-HT(6) receptor ligands. Within this class, several of the (R)-enantiomers were potent agonists having EC(50) values of 1 nM or less and functioning as full agonists while the (S)-enantiomers displayed moderate antagonist activity.
Subject(s)
Indoles/chemical synthesis , Pyrrolidines/chemical synthesis , Receptors, Serotonin/drug effects , Sulfonamides/chemical synthesis , Cyclic AMP/agonists , Cyclic AMP/antagonists & inhibitors , Cyclic AMP/biosynthesis , HeLa Cells , Humans , Indoles/chemistry , Indoles/pharmacology , Pyrrolidines/chemistry , Pyrrolidines/pharmacology , Stereoisomerism , Structure-Activity Relationship , Sulfonamides/chemistry , Sulfonamides/pharmacologyABSTRACT
Novel 1-(2-aminoethyl)-3-(arylsulfonyl)-1H-indoles were prepared. Binding assays indicated they are 5-HT(6) receptor ligands, among which N,N-dimethyl-N-(2-[3-(1-naphthylsulfonyl)-1H-indol-1-yl]ethyl)amine 8t and N-methyl-N-(2-[3-(1-naphthylsulfonyl)-1H-indol-1-yl]ethyl)amine 8u showed high affinity for 5-HT(6) receptors with K(i)=3.7 and 5.7 nM, respectively.
Subject(s)
Indoles/chemical synthesis , Indoles/pharmacology , Receptors, Serotonin/drug effects , Amines/chemical synthesis , Amines/pharmacology , Binding, Competitive , HeLa Cells , Humans , Ligands , Molecular Structure , Receptors, Serotonin/physiology , Structure-Activity RelationshipABSTRACT
Evaluation of selected compounds from our Corporate Compound Library in a human 5-HT(2C) receptor binding assay led to the discovery of WAY-629, a cyclohexyl[b][1,4]benzodiazepinoindole (K(i) 56 nM, E(max) 90%), which is selective for the 5-HT(2C) receptor versus other serotonin receptor subtypes, and dopamine, histamine, adrenergic, and muscarinic receptors. In addition, WAY-629 was active in vivo in a rat model of feeding behavior. An SAR study based on WAY-629 led to compound 11 (K(i) 13 nM, E(max) 102%).
Subject(s)
Indoles/pharmacology , Serotonin 5-HT2 Receptor Agonists , Serotonin Receptor Agonists/chemical synthesis , Animals , Benzodiazepines/chemical synthesis , Benzodiazepines/pharmacology , Feeding Behavior/drug effects , Humans , Indoles/chemical synthesis , Rats , Serotonin Receptor Agonists/pharmacology , Structure-Activity RelationshipABSTRACT
Novel tricyclic benzazepine derivatives were synthesized as arginine vasopressin (AVP) antagonists. Several tricyclic compounds showed potent antagonistic activity in rat AVP receptors V(1a) and V(2). Derivatives containing pyrrolo-tricyclic amines, 13i-k, 30, and 31 also showed selectivity for the V(2) receptor.
Subject(s)
Arginine Vasopressin/antagonists & inhibitors , Benzazepines/chemical synthesis , Benzazepines/pharmacology , Animals , Dose-Response Relationship, Drug , Indicators and Reagents , Kidney Medulla/drug effects , Kidney Medulla/metabolism , Liver/drug effects , Liver/metabolism , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Urodynamics/drug effectsABSTRACT
Based on the 7-OH-2-(aminomethyl)chroman dopamine D(2) template (2) is described the preparation and resolution of two bioisosteric analogues. The benzimidazol-2-one derivative (6) had similar affinity to the known indolone derivative (4).
