RESUMEN
A novel series of 5,5-diaryl-2-amino-4-pentenoates was synthesized and found to be potent and selective glycine transporter type-2 reuptake inhibitors.
Asunto(s)
Alquenos/farmacología , Sistemas de Transporte de Aminoácidos Neutros , Antimetabolitos/farmacología , Proteínas Portadoras/antagonistas & inhibidores , Alquenos/síntesis química , Alquenos/química , Antimetabolitos/síntesis química , Antimetabolitos/química , Proteínas de Transporte de Glicina en la Membrana Plasmática , Relación Estructura-ActividadRESUMEN
Sumatriptan, a h5-HT1D and h5-HT1B receptor agonist used clinically as a migraine-abortive, produces certain side effects thought to result from its affinity for h5-HT1B receptors. The present investigation extends our work with benzylimidazolines as novel non-tryptamine h5-HT(1D/1B) ligands. The effect of N-methylation, N-benzylation, ring-aromatization, and variation of the imidazoline ring on affinity both at h5-HT1D and h5-HT1B receptors was examined. Several compounds were identified with good affinity and enhanced (i.e., > 100-fold) h5-HT1D versus hS-HT1B selectivity.
Asunto(s)
Compuestos de Bencilo/farmacología , Imidazoles/farmacología , Receptores de Serotonina/metabolismo , Serotoninérgicos/síntesis química , Agonistas de Receptores de Serotonina/farmacología , Compuestos de Bencilo/síntesis química , Compuestos de Bencilo/metabolismo , Membrana Celular/química , Membrana Celular/metabolismo , Humanos , Imidazoles/síntesis química , Imidazoles/metabolismo , Ligandos , Trastornos Migrañosos/tratamiento farmacológico , Unión Proteica , Ensayo de Unión Radioligante , Receptor de Serotonina 5-HT1B , Receptor de Serotonina 5-HT1D , Serotoninérgicos/metabolismo , Serotoninérgicos/farmacologíaRESUMEN
N-Benzenesulfonyl-5-methoxy-N,N-dimethyltryptamine (BS/5-OMe DMT; 5) was shown to bind at human 5-HT6 serotonin receptors with high affinity (Ki = 2.3 nM) relative to serotonin (Ki = 78 nM). Structural variation failed to result in significantly enhanced affinity. BS/5-OMe DMT acts as an antagonist of 5-HT-stimulated adenylate cyclase (pA2 = 8.88 nM) and may represent the first member of a novel class of 5-HT6 antagonists.
Asunto(s)
Receptores de Serotonina/metabolismo , Antagonistas de la Serotonina/síntesis química , Triptaminas/síntesis química , Adenilil Ciclasas/metabolismo , Línea Celular , Diseño de Fármacos , Humanos , Cinética , Modelos Moleculares , Conformación Molecular , Ensayo de Unión Radioligante , Receptores de Serotonina/efectos de los fármacos , Proteínas Recombinantes/antagonistas & inhibidores , Antagonistas de la Serotonina/química , Antagonistas de la Serotonina/farmacología , Relación Estructura-Actividad , Transfección , Triptaminas/química , Triptaminas/farmacologíaRESUMEN
A series of 5-alkyltryptamines (6) and the corresponding conformationally constrained analogues (8) have been synthesized. The structure activity relationships (SAR) at the 5-position of the indole skeleton and the ethylamine side chain have been studied. Functional activities were assessed using isolated rabbit saphenous vein. Potent, selective ligands were found (6e, Ki 2.5 nM, 5-HT1B/5-HT1D 125-fold) that have potential for treating acute migraine.
Asunto(s)
Receptores de Serotonina/efectos de los fármacos , Agonistas de Receptores de Serotonina/farmacología , Triptaminas/química , Animales , Técnicas In Vitro , Unión Proteica , Conejos , Receptor de Serotonina 5-HT1D , Receptores de Serotonina/metabolismo , Vena Safena/efectos de los fármacos , Agonistas de Receptores de Serotonina/química , Agonistas de Receptores de Serotonina/metabolismo , Triptaminas/metabolismoRESUMEN
A novel series of 6-bicyclopiperazinyl-1-arylsulfonylindoles and 6-bicyclopiperidinyl-1-arylsulfonylindoles derivatives was synthesized and found to be potent and selective 5-HT6 receptor antagonists.
Asunto(s)
Indoles/farmacología , Receptores de Serotonina/efectos de los fármacos , Antagonistas de la Serotonina/farmacología , Línea Celular , Humanos , Indoles/síntesis química , Indoles/química , Indoles/metabolismo , Piperazinas/química , Ensayo de Unión Radioligante , Receptores de Serotonina/metabolismo , Antagonistas de la Serotonina/síntesis química , Antagonistas de la Serotonina/química , Sulfonas/químicaRESUMEN
A series of 5-(2- or 3-thienyl)tryptamine derivatives (9) has been synthesized and shown to be potent and selective 5-HT1D versus 5-HT1B receptor agonists and, therefore, potential treatments for migraine.
Asunto(s)
Trastornos Migrañosos/tratamiento farmacológico , Receptores de Serotonina/efectos de los fármacos , Antagonistas de la Serotonina/síntesis química , Triptaminas/síntesis química , Clonación Molecular , Humanos , Indicadores y Reactivos , Receptor de Serotonina 5-HT1B , Receptor de Serotonina 5-HT1D , Antagonistas de la Serotonina/farmacología , Relación Estructura-Actividad , Triptaminas/farmacologíaRESUMEN
A series of pyrrolo[3,2,1-ij]quinoline derivatives was synthesized, evaluated for their activity against the 5-HT2c and 5-HT2a, receptors and found to be agonists at 5-HT2c with selectivity over 5-HT2a.