RESUMO
Serotonin 5-HT6 receptor has been proposed as a promising therapeutic target for cognition enhancement though the development of new antagonists is still needed to validate these molecules as a drug class for the treatment of Alzheimer's disease and other pathologies associated with memory deficiency. As part of our efforts to target the 5-HT6 receptor, new benzimidazole-based compounds have been designed and synthesized. Site-directed mutagenesis and homology models show the importance of a halogen bond interaction between a chlorine atom of the new class of 5-HT6 receptor antagonists identified herein and a backbone carbonyl group in transmembrane domain 4. In vitro pharmacological characterization of 5-HT6 receptor antagonist 7 indicates high affinity and selectivity over a panel of receptors including 5-HT2B subtype and hERG channel, which suggests no major cardiac issues. Compound 7 exhibited in vivo procognitive activity (1 mg/kg, ip) in the novel object recognition task as a model of memory deficit.
Assuntos
Cognição/efeitos dos fármacos , Halogênios/química , Receptores de Serotonina/metabolismo , Antagonistas da Serotonina/farmacologia , Animais , Benzimidazóis/síntese química , Benzimidazóis/química , Benzimidazóis/farmacologia , Humanos , Ligantes , Microssomos Hepáticos/metabolismo , Mutagênese Sítio-Dirigida , Ratos , Receptores de Serotonina/química , Antagonistas da Serotonina/síntese química , Antagonistas da Serotonina/química , Homologia Estrutural de Proteína , Análise e Desempenho de TarefasRESUMO
The finding that ergotamine binds serotonin receptors in a less conserved extended binding pocket close to the extracellular entrance, in addition to the orthosteric site, allowed us to obtain 5-HT7R antagonist 6 endowed with high affinity (Ki=0.7 nM) and significant 5-HT1AR selectivity (ratio>1428). Compound 6 exhibits in vivo antidepressant-like effect (1 mg/kg, ip) mediated by the 5-HT7R, which reveals its interest as a putative research tool or pharmaceutical in depression disorders.
Assuntos
Antidepressivos/química , Indóis/química , Isoquinolinas/química , Receptores de Serotonina/metabolismo , Antagonistas da Serotonina/química , Animais , Antidepressivos/síntese química , Antidepressivos/farmacologia , Temperatura Corporal/efeitos dos fármacos , Feminino , Hipotermia/induzido quimicamente , Indóis/síntese química , Indóis/farmacologia , Isoquinolinas/síntese química , Isoquinolinas/farmacologia , Masculino , Camundongos Endogâmicos C57BL , Simulação de Dinâmica Molecular , Atividade Motora/efeitos dos fármacos , Antagonistas da Serotonina/síntese química , Antagonistas da Serotonina/farmacologia , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
On the basis of our previously described pharmacophore model for serotonin 5-HT(6) receptor (5-HT(6)R) antagonists, we have designed, synthesized, and pharmacologically characterized a series of benzimidazole derivatives 1-20 that represent a new family of potent antagonists at the human 5-HT(6)R. Site-directed mutagenesis and a beta(2)-adrenoceptor-based homology model of the 5-HT(6)R were used to predict the mode of binding of antagonist SB-258585 and the new synthesized ligands. Substitution of W6.48, F6.52, or N6.55 by Ala fully impedes compound 4 to block 5-HT-induced activation. Thus, we propose that D3.32 in TM 3 anchors the protonated piperazine ring, the benzimidazole ring expands parallel to EL 2 to hydrogen bond N6.55 in TM 6, and the aromatic ring is placed between TMs 3 and 5 in CH(2)-containing compounds and between TMs 3 and 6 in CO-containing compounds. This combined experimental and computational study has permitted to propose the molecular mechanisms by which the new benzimidazole derivatives act as 5-HT(6)R antagonists.
Assuntos
Benzimidazóis/química , Benzimidazóis/farmacologia , Receptores de Serotonina/química , Receptores de Serotonina/metabolismo , Antagonistas da Serotonina/síntese química , Animais , Benzimidazóis/síntese química , Ligação Competitiva , Células COS , Células Cultivadas , Chlorocebus aethiops , Simulação por Computador , AMP Cíclico/metabolismo , Ensaio de Imunoadsorção Enzimática , Humanos , Rim/citologia , Rim/efeitos dos fármacos , Estrutura Molecular , Mutagênese Sítio-Dirigida , Conformação Proteica , Ensaio Radioligante , Receptores de Serotonina/genética , Antagonistas da Serotonina/química , Antagonistas da Serotonina/farmacologia , Relação Estrutura-AtividadeRESUMO
Forty-five structurally diverse 5-hydroxytryptamine(6) receptor (5-HT(6)R) antagonists were selected to develop a 3D pharmacophore model with the Catalyst software. The structural features for antagonism at this receptor are a positive ionizable atom interacting with Asp(3.32), a hydrogen bond acceptor group interacting with Ser(5.43) and Asn(6.55), a hydrophobic site interacting with residues in a hydrophobic pocket between transmembranes 3, 4, and 5, and an aromatic-ring hydrophobic site interacting with Phe(6.52).
