RESUMO
Several benzofuran derivatives linked to a 3-indoletetrahydropyridine through an alkyl chain were prepared and evaluated for serotonin transporter and 5-HT(1A) receptor affinities. Their design, synthesis and structure-activity relationships are described.
Assuntos
Benzofuranos/química , Benzofuranos/metabolismo , Receptor 5-HT1A de Serotonina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Animais , Células CHO , Cricetinae , Cricetulus , Humanos , Ligação Proteica/fisiologia , Relação Estrutura-AtividadeRESUMO
On the basis of the previously reported clinical candidate, SSA-426 (1), a series of related 2-piperazin-1-ylquinoline derivatives 3-16 were synthesized and evaluated as dual-acting serotonin (5-HT) reuptake inhibitors and 5-HT1A receptor antagonists. In particular, compound 7 exhibits potent functional activities at both the 5-HT transporter and 5-HT1A receptor, good selectivity over the alpha1-adrenergic and dopaminergic receptors, acceptable pharmacokinetic properties, and a favorable in vivo profile.
Assuntos
Piperazinas/síntese química , Quinolinas/síntese química , Inibidores Seletivos de Recaptação de Serotonina/síntese química , Antagonistas do Receptor 5-HT1 de Serotonina , Antagonistas da Serotonina/síntese química , Animais , Antidepressivos/farmacologia , Células CHO , Cricetinae , Cricetulus , Inibidores das Enzimas do Citocromo P-450 , Humanos , Microdiálise , Piperazinas/farmacologia , Quinolinas/farmacologia , Ratos , Receptores Adrenérgicos alfa 1/metabolismo , Receptores Dopaminérgicos/metabolismo , Antagonistas da Serotonina/farmacocinética , Antagonistas da Serotonina/farmacologia , Inibidores Seletivos de Recaptação de Serotonina/farmacocinética , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Relação Estrutura-AtividadeRESUMO
Based on the previously reported discovery lead, 3-(cis-4-(4-(1H-indol-4-yl)piperazin-1-yl)cyclohexyl)-5-fluoro-1H-indole (2), a series of related arylpiperazin-4-yl-cyclohexyl indole analogs were synthesized then evaluated as 5-HT transporter inhibitors and 5-HT(1A) receptor antagonists. The investigation of the structure-activity relationships revealed the optimal pharmacophoric elements required for activities in this series. The best example from this study, 5-(piperazin-1-yl)quinoline analog (trans-20), exhibited equal binding affinities at 5-HT transporter (K(i)=4.9nM), 5-HT(1A) receptor (K(i)=6.2nM) and functioned as a 5-HT(1A) receptor antagonist.
Assuntos
Antidepressivos/química , Indóis/química , Receptor 5-HT1A de Serotonina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Animais , Cicloexilaminas , Humanos , Indóis/metabolismo , Indóis/farmacologia , Piperazinas , Antagonistas do Receptor 5-HT1 de Serotonina , Relação Estrutura-AtividadeRESUMO
The design, synthesis, and structure-activity relationship of two novel classes of benzoxazine derivatives with dual selective serotonin reuptake inhibitors and 5-HT(1A) receptor activities are described.
Assuntos
Antidepressivos/síntese química , Antidepressivos/metabolismo , Benzoxazinas/química , Benzoxazinas/metabolismo , Receptor 5-HT1A de Serotonina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Animais , Antidepressivos/química , Antidepressivos/farmacologia , Benzoxazinas/síntese química , Benzoxazinas/farmacologia , Humanos , Estrutura Molecular , Ratos , Relação Estrutura-Atividade , Especificidade por SubstratoRESUMO
Derivatives of the serotonin reuptake inhibitor 4-(5-fluoro-1H-indol-3-yl)cyclohexylamine, in which serotonin 1A (5-HT(1A)) receptor pharmacophoric elements are incorporated, are reported. Analogs exhibiting affinity for both the serotonin transporter and the 5-HT(1A) receptor are described. Compounds containing 1-(4-indolyl)piperazine and 2-(1H-indol-4-yloxy)ethylamine are promising leads for further SAR studies.
