RESUMO
A 3D pharmacophore model predicting anticonvulsant activity was obtained for a series of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline derivatives recently disclosed as a new class of noncompetitive AMPA receptor antagonists. The training set included 17 compounds with varying potency against audiogenic seizures in DBA/2 mice. The best statistical hypothesis, generated with the HypoGen module of Catalyst 4.9, consisted of five features: two hydrogen bond acceptors, two hydrophobic features, and one hydrophobic aromatic region, providing a model with a correlation coefficient of 0.919. The obtained model was an efficient tool in the design of some new anticonvulsant agents containing the tetrahydroisoquinoline scaffold. Moreover, in order to explain the different degree of efficacy of the newly designed N-substituted derivatives, excluded volumes were also considered.
Assuntos
Anticonvulsivantes/química , Modelos Moleculares , Tetra-Hidroisoquinolinas/química , Animais , Anticonvulsivantes/farmacologia , Anticonvulsivantes/uso terapêutico , Benzodiazepinas/química , Benzodiazepinas/farmacologia , Benzodiazepinas/uso terapêutico , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Epilepsia Reflexa/induzido quimicamente , Epilepsia Reflexa/prevenção & controle , Feminino , Isoquinolinas/química , Isoquinolinas/farmacologia , Isoquinolinas/uso terapêutico , Masculino , Camundongos , Camundongos Endogâmicos DBA , Modelos Animais , Conformação Molecular , Estrutura Molecular , Relação Estrutura-Atividade , Tetra-Hidroisoquinolinas/farmacologia , Tetra-Hidroisoquinolinas/uso terapêuticoRESUMO
As a follow up of our previous structure-activity relationship and molecular modeling studies, we synthesized a novel series of 1-aryl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline derivatives as potential non-competitive AMPA receptor antagonists. When tested for their ability to prevent sound-induced seizures in DBA/2 mice, some of these novel compounds showed high anticonvulsant potency.
Assuntos
Anticonvulsivantes/síntese química , Anticonvulsivantes/farmacologia , Convulsões/prevenção & controle , Tetra-Hidroisoquinolinas/síntese química , Tetra-Hidroisoquinolinas/farmacologia , Animais , Benzodiazepinas/farmacologia , Benzodiazepinonas/farmacologia , Avaliação Pré-Clínica de Medicamentos , Antagonistas de Aminoácidos Excitatórios/farmacologia , Feminino , Masculino , Camundongos , Camundongos Endogâmicos DBA , Modelos Moleculares , Estrutura Molecular , Receptores de AMPA/antagonistas & inibidores , Relação Estrutura-AtividadeRESUMO
N-Acetyl-1-aryl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline derivatives were designed and synthesized as potential noncompetitive AMPA receptor antagonists on the basis of molecular modeling studies. Sound-induced seizure testing showed that this class of compounds possessed anticonvulsant properties. In particular, 10c was more potent than talampanel (2), a noncompetitive AMPA receptor antagonist currently being investigated in phase III trials as an antiepileptic agent. Furthermore, electrophysiological studies indicated that 10c was a highly effective noncompetitive-type modulator of the AMPA receptor.