RESUMO
Herein, we report the synthesis and structure-activity relationship of a series of chiral alkoxymethyl morpholine analogs. Our efforts have culminated in the identification of (S)-2-(((6-chloropyridin-2-yl)oxy)methyl)-4-((6-fluoro-1H-indol-3-yl)methyl)morpholine as a novel potent and selective dopamine D4 receptor antagonist with selectivity against the other dopamine receptors tested (<10% inhibition at 1µM against D1, D2L, D2S, D3, and D5).
Assuntos
Antagonistas de Dopamina/química , Antagonistas de Dopamina/farmacologia , Morfolinas/química , Receptores de Dopamina D4/antagonistas & inibidores , Relação Estrutura-Atividade , Animais , Antagonistas de Dopamina/síntese química , Avaliação Pré-Clínica de Medicamentos/métodos , Humanos , Microssomos Hepáticos/efeitos dos fármacos , RatosRESUMO
Herein, we report the synthesis and structure-activity relationship of a novel series of (R)-4,4-difluoropiperidine core scaffold as dopamine receptor 4 (D4) antagonists. A series of compounds from this scaffold are highly potent against the D4 receptor and selective against the other dopamine receptors. In addition, we were able to confirm the active isomer as the (R)-enantiomer via an X-ray crystal structure.
