RESUMO
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.
Assuntos
Antipsicóticos/metabolismo , Antipsicóticos/farmacologia , Compostos Heterocíclicos de 4 ou mais Anéis/metabolismo , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Receptor 5-HT2C de Serotonina/metabolismo , Agonistas do Receptor 5-HT2 de Serotonina/metabolismo , Agonistas do Receptor 5-HT2 de Serotonina/farmacologia , Animais , Sítios de Ligação/efeitos dos fármacos , Células CHO , Linhagem Celular , Cricetinae , Cricetulus , Humanos , Masculino , Terapia de Alvo Molecular , Contração Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Músculo Liso/fisiologia , Ligação Proteica/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptor 5-HT2A de Serotonina/metabolismo , Receptor 5-HT2B de Serotonina/metabolismo , Proteínas Recombinantes/metabolismo , Serotonina/análogos & derivados , Serotonina/metabolismo , Antagonistas do Receptor 5-HT2 de Serotonina/metabolismo , Antagonistas do Receptor 5-HT2 de Serotonina/farmacologia , Transdução de Sinais/efeitos dos fármacosRESUMO
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.
Assuntos
Piridinas/farmacologia , Pirróis/farmacologia , Receptores de Serotonina/efeitos dos fármacos , Antagonistas da Serotonina/farmacologia , Agonistas do Receptor de Serotonina/farmacologia , Células HeLa , Humanos , Ligantes , Piridinas/química , Pirróis/química , Receptores de Serotonina/metabolismo , Antagonistas da Serotonina/química , Agonistas do Receptor de Serotonina/químicaRESUMO
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.
Assuntos
Córtex Cerebral/efeitos dos fármacos , Comportamento de Ingestão de Líquido/efeitos dos fármacos , Receptores de Serotonina/metabolismo , Agonistas do Receptor de Serotonina/química , Agonistas do Receptor de Serotonina/farmacologia , Animais , Córtex Cerebral/metabolismo , Ácido Glutâmico/análise , Ácido Glutâmico/metabolismo , Células HeLa , Humanos , Ligação Proteica , Ratos , Agonistas do Receptor de Serotonina/administração & dosagem , Agonistas do Receptor de Serotonina/síntese química , Ácido gama-Aminobutírico/análise , Ácido gama-Aminobutírico/metabolismoRESUMO
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.
Assuntos
Receptores de Serotonina/metabolismo , Agonistas do Receptor de Serotonina/síntese química , Tiazóis/química , Triptaminas/síntese química , Administração Oral , Animais , Disponibilidade Biológica , Células CHO , Cricetinae , Cricetulus , Cães , Lobo Frontal/metabolismo , Haplorrinos , Humanos , Técnicas In Vitro , Camundongos , Microdiálise , Microssomos Hepáticos/metabolismo , Ensaio Radioligante , Ratos , Agonistas do Receptor de Serotonina/farmacocinética , Agonistas do Receptor de Serotonina/farmacologia , Solubilidade , Relação Estrutura-Atividade , Tiazóis/farmacocinética , Tiazóis/farmacologia , Triptaminas/química , Triptaminas/farmacocinética , Triptaminas/farmacologia , Ácido gama-Aminobutírico/metabolismoRESUMO
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.
Assuntos
Benzodiazepinas/síntese química , Benzodiazepinas/farmacologia , Pirróis/síntese química , Pirróis/farmacologia , Receptores de Vasopressinas/metabolismo , Antagonistas dos Receptores de Hormônios Antidiuréticos , Benzodiazepinas/química , Plaquetas/efeitos dos fármacos , Plaquetas/metabolismo , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Pirróis/química , Sensibilidade e Especificidade , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Indóis/síntese química , Pirrolidinas/síntese química , Receptores de Serotonina/efeitos dos fármacos , Sulfonamidas/síntese química , AMP Cíclico/agonistas , AMP Cíclico/antagonistas & inibidores , AMP Cíclico/biossíntese , Células HeLa , Humanos , Indóis/química , Indóis/farmacologia , Pirrolidinas/química , Pirrolidinas/farmacologia , Estereoisomerismo , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacologiaRESUMO
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.
Assuntos
Indóis/síntese química , Indóis/farmacologia , Receptores de Serotonina/efeitos dos fármacos , Aminas/síntese química , Aminas/farmacologia , Ligação Competitiva , Células HeLa , Humanos , Ligantes , Estrutura Molecular , Receptores de Serotonina/fisiologia , Relação Estrutura-AtividadeRESUMO
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%).
Assuntos
Indóis/farmacologia , Agonistas do Receptor 5-HT2 de Serotonina , Agonistas do Receptor de Serotonina/síntese química , Animais , Benzodiazepinas/síntese química , Benzodiazepinas/farmacologia , Comportamento Alimentar/efeitos dos fármacos , Humanos , Indóis/síntese química , Ratos , Agonistas do Receptor de Serotonina/farmacologia , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Arginina Vasopressina/antagonistas & inibidores , Benzazepinas/síntese química , Benzazepinas/farmacologia , Animais , Relação Dose-Resposta a Droga , Indicadores e Reagentes , Medula Renal/efeitos dos fármacos , Medula Renal/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Urodinâmica/efeitos dos fármacosRESUMO
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).