RESUMEN
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.
Asunto(s)
Antipsicóticos/metabolismo , Antipsicóticos/farmacología , Compuestos Heterocíclicos de 4 o más Anillos/metabolismo , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Receptor de Serotonina 5-HT2C/metabolismo , Agonistas del Receptor de Serotonina 5-HT2/metabolismo , Agonistas del Receptor de Serotonina 5-HT2/farmacología , Animales , Sitios de Unión/efectos de los fármacos , Células CHO , Línea Celular , Cricetinae , Cricetulus , Humanos , Masculino , Terapia Molecular Dirigida , Contracción Muscular/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Músculo Liso/fisiología , Unión Proteica/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Receptor de Serotonina 5-HT2A/metabolismo , Receptor de Serotonina 5-HT2B/metabolismo , Proteínas Recombinantes/metabolismo , Serotonina/análogos & derivados , Serotonina/metabolismo , Antagonistas del Receptor de Serotonina 5-HT2/metabolismo , Antagonistas del Receptor de Serotonina 5-HT2/farmacología , Transducción de Señal/efectos de los fármacosRESUMEN
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.
Asunto(s)
Piridinas/farmacología , Pirroles/farmacología , Receptores de Serotonina/efectos de los fármacos , Antagonistas de la Serotonina/farmacología , Agonistas de Receptores de Serotonina/farmacología , Células HeLa , Humanos , Ligandos , Piridinas/química , Pirroles/química , Receptores de Serotonina/metabolismo , Antagonistas de la Serotonina/química , Agonistas de Receptores de Serotonina/químicaRESUMEN
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.
Asunto(s)
Corteza Cerebral/efectos de los fármacos , Conducta de Ingestión de Líquido/efectos de los fármacos , Receptores de Serotonina/metabolismo , Agonistas de Receptores de Serotonina/química , Agonistas de Receptores de Serotonina/farmacología , Animales , Corteza Cerebral/metabolismo , Ácido Glutámico/análisis , Ácido Glutámico/metabolismo , Células HeLa , Humanos , Unión Proteica , Ratas , Agonistas de Receptores de Serotonina/administración & dosificación , Agonistas de Receptores de Serotonina/síntesis química , Ácido gamma-Aminobutírico/análisis , Ácido gamma-Aminobutírico/metabolismoRESUMEN
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.
Asunto(s)
Receptores de Serotonina/metabolismo , Agonistas de Receptores de Serotonina/síntesis química , Tiazoles/química , Triptaminas/síntesis química , Administración Oral , Animales , Disponibilidad Biológica , Células CHO , Cricetinae , Cricetulus , Perros , Lóbulo Frontal/metabolismo , Haplorrinos , Humanos , Técnicas In Vitro , Ratones , Microdiálisis , Microsomas Hepáticos/metabolismo , Ensayo de Unión Radioligante , Ratas , Agonistas de Receptores de Serotonina/farmacocinética , Agonistas de Receptores de Serotonina/farmacología , Solubilidad , Relación Estructura-Actividad , Tiazoles/farmacocinética , Tiazoles/farmacología , Triptaminas/química , Triptaminas/farmacocinética , Triptaminas/farmacología , Ácido gamma-Aminobutírico/metabolismoRESUMEN
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.
Asunto(s)
Indoles/síntesis química , Pirrolidinas/síntesis química , Receptores de Serotonina/efectos de los fármacos , Sulfonamidas/síntesis química , AMP Cíclico/agonistas , AMP Cíclico/antagonistas & inhibidores , AMP Cíclico/biosíntesis , Células HeLa , Humanos , Indoles/química , Indoles/farmacología , Pirrolidinas/química , Pirrolidinas/farmacología , Estereoisomerismo , Relación Estructura-Actividad , Sulfonamidas/química , Sulfonamidas/farmacologíaRESUMEN
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.
Asunto(s)
Benzodiazepinas/síntesis química , Benzodiazepinas/farmacología , Pirroles/síntesis química , Pirroles/farmacología , Receptores de Vasopresinas/metabolismo , Antagonistas de los Receptores de Hormonas Antidiuréticas , Benzodiazepinas/química , Plaquetas/efectos de los fármacos , Plaquetas/metabolismo , Humanos , Concentración 50 Inhibidora , Estructura Molecular , Pirroles/química , Sensibilidad y Especificidad , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Indoles/síntesis química , Indoles/farmacología , Receptores de Serotonina/efectos de los fármacos , Aminas/síntesis química , Aminas/farmacología , Unión Competitiva , Células HeLa , Humanos , Ligandos , Estructura Molecular , Receptores de Serotonina/fisiología , Relación Estructura-ActividadRESUMEN
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).
Asunto(s)
Benzopiranos/química , Agonistas de Dopamina/química , Receptores de Dopamina D2/química , Benzopiranos/síntesis química , Agonistas de Dopamina/síntesis química , Modelos Estructurales , Receptores de Dopamina D2/administración & dosificación , Relación Estructura-Actividad , Moldes GenéticosRESUMEN
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%).
Asunto(s)
Indoles/farmacología , Agonistas del Receptor de Serotonina 5-HT2 , Agonistas de Receptores de Serotonina/síntesis química , Animales , Benzodiazepinas/síntesis química , Benzodiazepinas/farmacología , Conducta Alimentaria/efectos de los fármacos , Humanos , Indoles/síntesis química , Ratas , Agonistas de Receptores de Serotonina/farmacología , Relación Estructura-ActividadRESUMEN
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.