RESUMO
Within a series of histamine H(3)-antagonists characterized by a biphenyl core and two basic groups, we identified (S)-1-{[4'-((2-methylpyrrolidin-1-yl)methyl)biphenyl-4-yl]methyl}piperidine as a lead scaffold to introduce an additional lipophilic chain at the benzylic carbon close to the pyrrolidine ring. A series of derivatives was synthesized and tested for their binding affinity at human and rat histamine H(3) receptors, and for their antagonist potency. For compounds with two chiral centers, the synthetic procedure provided mixtures of diastereomeric couples, which were separated by flash chromatography. Combination of experimental NMR data and molecular dynamics simulation allowed the assignment of absolute stereochemistry, based on characteristic differences detected within each diastereomeric couple. The additional lipophilic group was tolerated by the receptor, supporting the hypothesis that the two regions described within the H(3) receptor binding site can be simultaneously occupied by antagonists. Diastereoisomers with opposite chirality at the benzylic carbon showed limited or no stereoselectivity at both human and rat receptors.
Assuntos
Compostos de Bifenilo/química , Antagonistas dos Receptores Histamínicos/química , Piperidinas/química , Pirrolidinas/química , Receptores Histamínicos H3/metabolismo , Animais , Ligação Competitiva , Compostos de Bifenilo/síntese química , Compostos de Bifenilo/farmacologia , Linhagem Celular , Antagonistas dos Receptores Histamínicos/síntese química , Antagonistas dos Receptores Histamínicos/farmacologia , Humanos , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Modelos Moleculares , Simulação de Dinâmica Molecular , Piperidinas/síntese química , Piperidinas/farmacologia , Pirrolidinas/síntese química , Pirrolidinas/farmacologia , Ratos , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Diastereomeric salts with optically pure (S)-alpha-methoxy-alpha-(trifluoromethyl)phenylacetic acid (MTPA) were used to discriminate the enantiomers of the chiral H(3)-antagonist 2-[3-(1H-imidazol-4-ylmethyl)piperidin-1-yl]-1H-benzimidazole. Chemical-shift differences (Delta delta) in NMR spectra strongly depend on solvent and stoichiometric ratio. The better observable differentiation occurred for the proton at the 2-position of the imidazole ring.