RESUMEN
Research in Alzheimer's disease is going through a big turnaround. New palliative therapies are being reconsidered for the effective management of disease because of setbacks in the development of disease-modifying therapies. Serotonin 6 (5-HT6) receptor has long been pursued as a potential target for the symptomatic treatment of Alzheimer's disease. SUVN-502 is a novel 5-HT6 receptor antagonist (Ki=2.04 nmol/l) with high receptor affinity and high degree of selectivity. SUVN-502 at doses ranging from 1 to 10 mg/kg, per os (p.o.) demonstrated procognitive effects in various behavioral animal models (object recognition task, water maze, and radial arm maze), and it acts on three phases of cognition, viz., acquisition, consolidation, and retention (object recognition task). SUVN-502 (3 and 10 mg/kg, p.o.) modulated glutamate levels when administered alone (microdialysis). At doses ranging from 1 to 10 mg/kg p.o., SUVN-502 potentiated the effects of donepezil (microdialysis). SUVN-502 [1 mg/kg, intravenous (i.v.)] also potentiated pharmacological effects of memantine (1 mg/kg, i.v.) and/or donepezil (0.3 mg/kg, i.v.) (θ modulation). The beneficial effects of SUVN-502 on learning and memory might be mediated through the modulation of cholinergic and/or glutamatergic neurotransmission in relevant brain regions. In summary, behavioral, neurochemical, and electrophysiological outcomes indicate that SUVN-502 may augment the beneficial effects of donepezil and memantine combination.
Asunto(s)
Conducta Animal/efectos de los fármacos , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Indoles/farmacología , Piperazinas/farmacología , Antagonistas de la Serotonina/farmacología , Acetilcolina/farmacología , Animales , Ondas Encefálicas/efectos de los fármacos , Células CHO , Cricetulus , Medio de Cultivo Libre de Suero/farmacología , Maleato de Dizocilpina/farmacología , Donepezilo/farmacología , Relación Dosis-Respuesta a Droga , Electroencefalografía , Ácido Glutámico/farmacología , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Memantina/farmacología , Trastornos de la Memoria/inducido químicamente , Trastornos de la Memoria/tratamiento farmacológico , Microdiálisis , Nootrópicos/farmacología , Ratas , Ratas Wistar , Receptores de Serotonina/metabolismo , Reconocimiento en Psicología/efectos de los fármacos , Escopolamina/toxicidad , Serotonina/metabolismoRESUMEN
The design, synthesis and SAR of novel tetrahydrocarbazole derivatives having 5-HT(6) receptor antagonist activity is presented. The racemic compound 15e was found to possess desirable pharmacokinetic properties, adequate brain penetration and activity in animal models of cognition.
Asunto(s)
Aminas/química , Carbazoles/química , Receptores de Serotonina/química , Antagonistas de la Serotonina/química , Sulfonamidas/química , Aminas/síntesis química , Aminas/farmacocinética , Animales , Encéfalo/metabolismo , Carbazoles/síntesis química , Carbazoles/farmacocinética , Semivida , Humanos , Masculino , Microsomas Hepáticos/metabolismo , Ratas , Ratas Wistar , Receptores de Serotonina/metabolismo , Antagonistas de la Serotonina/síntesis química , Antagonistas de la Serotonina/farmacocinética , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/farmacocinéticaRESUMEN
A series of N(1)-arylsulfonyl-3-(pyrrolidin-3-yl)-1H-indole and N(1)-arylsulfonyl-3-(4-chloro-2,5-dihydro-1H-pyrrol-3-yl)-1H-indole derivatives (tryptamine derivatives with rigidized side chain) have been prepared and tested for their binding affinity to 5-HT(6) receptor. Several compounds displayed potent binding affinity for the 5-HT(6) receptor when tested in in vitro binding assay. The primary SAR indicates that rigidification of dimethylamino alkyl chain at C(3) of indole carbon maintains the binding affinity to 5-HT(6)R. The lead compound N(1)-benzenesulfonyl-3-(4-chloro-1-methyl-2,5-dihydro-1H-pyrrol-3-yl)-1H-indole, 10a (K(b)=0.1 nM) has shown excellent in vitro affinity and was active in animal models of cognition like NORT and water maze.
