RESUMEN
Bicyclic acidic amino acids (+/-)-6 and (+/-)-7, which are conformationally constrained homologues of glutamic acid, were prepared via a strategy based on a 1,3-dipolar cycloaddition. The new amino acids were tested toward ionotropic and metabotropic glutamate receptor subtypes; both of them behaved as antagonists at mGluR1,5 and as agonists at mGluR2. Furthermore, whereas (+/-)-6 was inactive at all ionotropic glutamate receptors, (+/-)-7 displayed a quite potent antagonism at the NMDA receptors. In the in vivo tests on DBA/2 mice, the compounds displayed an anticonvulsant activity. The interesting pharmacological profile of (+/-)-7 qualifies it as a lead of novel neuroprotective agents.
Asunto(s)
Aminoácidos Acídicos/síntesis química , Aminoácidos Dicarboxílicos/síntesis química , Anticonvulsivantes/síntesis química , Ácidos Dicarboxílicos/síntesis química , Compuestos Heterocíclicos con 2 Anillos/síntesis química , Isoxazoles/síntesis química , Aminoácidos Acídicos/química , Aminoácidos Acídicos/farmacología , Aminoácidos Dicarboxílicos/química , Aminoácidos Dicarboxílicos/farmacología , Animales , Anticonvulsivantes/química , Anticonvulsivantes/farmacología , Células CHO , Corteza Cerebral/metabolismo , Cricetinae , Cristalografía por Rayos X , Ácidos Dicarboxílicos/química , Ácidos Dicarboxílicos/farmacología , Agonistas de Aminoácidos Excitadores/síntesis química , Agonistas de Aminoácidos Excitadores/química , Agonistas de Aminoácidos Excitadores/farmacología , Antagonistas de Aminoácidos Excitadores/síntesis química , Antagonistas de Aminoácidos Excitadores/química , Antagonistas de Aminoácidos Excitadores/farmacología , Compuestos Heterocíclicos con 2 Anillos/química , Compuestos Heterocíclicos con 2 Anillos/farmacología , Técnicas In Vitro , Isoxazoles/química , Isoxazoles/farmacología , Masculino , Ratones , Ratones Endogámicos DBA , Conformación Molecular , Ratas , Receptor del Glutamato Metabotropico 5 , Receptores de Glutamato Metabotrópico/agonistas , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , EstereoisomerismoRESUMEN
A 39-member library of bile acid derivatives was prepared starting from 3alpha,7alpha,12alpha-trihydroxy-5beta-cholan-24-oic acid methyl ester using a combinatorial biocatalytic approach. A regioselective oxidation step, catalyzed by hydroxysteroid dehydrogenases, followed by an acylation step with a series of different acyl donors catalyzed by Candida antarctica lipase B, led to the modification of the bile acid scaffold. Each member of the library was obtained in high purity and good yield.