RESUMO
As part of our efforts to develop agents for cognitive enhancement, we have been focused on the 5-HT(6) receptor in order to identify potent and selective ligands for this purpose. Herein we report the identification of a novel series of 3-sulfonylindazole derivatives with acyclic amino side chains as potent and selective 5-HT(6) antagonists. The synthesis and detailed SAR of this class of compounds are reported.
Assuntos
Indazóis/farmacologia , Receptores de Serotonina/efeitos dos fármacos , Antagonistas da Serotonina/farmacologia , Células HeLa , Humanos , Indazóis/química , Espectroscopia de Ressonância Magnética , Nootrópicos/química , Nootrópicos/farmacologia , Antagonistas da Serotonina/química , Espectrometria de Massas por Ionização por Electrospray , Relação Estrutura-AtividadeRESUMO
Novel 5-cyclic amine-3-arylsulfonylindazoles were prepared, and several analogues within this class have been identified as high-affinity 5-HT(6) receptor ligands with improved pharmacokinetic and pharmacological properties. One selected example, 18b, showed good brain penetrability and a generally favorable pharmacokinetic profile with procognitive efficacy in the rat novel object recognition assay. The synthesis and structure-activity relationship of this potent class are discussed.
Assuntos
Indazóis/metabolismo , Receptores de Serotonina/metabolismo , Antagonistas da Serotonina/metabolismo , Sulfonas/metabolismo , Animais , Ligação Competitiva , Encéfalo/metabolismo , Comportamento Exploratório/efeitos dos fármacos , Habituação Psicofisiológica/efeitos dos fármacos , Humanos , Indazóis/química , Indazóis/farmacologia , Modelos Químicos , Estrutura Molecular , Ratos , Receptor 5-HT2B de Serotonina/química , Receptor 5-HT2B de Serotonina/metabolismo , Receptores de Serotonina/química , Reconhecimento Psicológico/efeitos dos fármacos , Antagonistas do Receptor 5-HT2 de Serotonina , Antagonistas da Serotonina/química , Antagonistas da Serotonina/farmacocinética , Relação Estrutura-Atividade , Sulfonas/química , Sulfonas/farmacologiaRESUMO
Synthesis of 2,3-substituted indoles from phenylhydrazine and alpha-branched aldehydes via rearrangement of 3,3-disubstituted indolenine intermediates is reported. [reaction: see text]
Assuntos
Indóis/síntese química , Aldeídos/química , Catálise , Espectroscopia de Ressonância Magnética , Fenil-Hidrazinas/química , SolventesRESUMO
Compounds containing a 5-carbamoyl-8-fluoro-3-amino-3,4-dihydro-2H-1-benzopyran and a 3-alkylindole moiety linked through a common basic nitrogen were prepared and evaluated for 5-HT1A affinity, serotonin rat transporter affinity, and functional antagonist activity in vitro. 26a was found to be the most potent and selective compound in this series and was shown to possess neurochemical activity in vivo by producing acute and rapid increases in 5-HT in the rat frontal cortex.