RESUMO
The development of a series of GABA(A) alpha2/alpha3 subtype selective pyridazine based benzodiazepine site agonists as anxiolytic agents with reduced sedative/ataxic potential is described, including the discovery of 16, a remarkably alpha3-selective compound ideal for in vivo study. These ligands are antagonists at the alpha1 subtype, with good CNS penetration and receptor occupancy, and excellent oral bioavailability.
Assuntos
Ansiolíticos/farmacologia , Ansiedade/tratamento farmacológico , Agonistas GABAérgicos/farmacologia , Agonistas de Receptores de GABA-A , Piridazinas/farmacologia , Animais , Ansiolíticos/administração & dosagem , Ansiolíticos/síntese química , Sítios de Ligação , Agonistas GABAérgicos/administração & dosagem , Agonistas GABAérgicos/síntese química , Humanos , Ligantes , Estrutura Molecular , Piridazinas/administração & dosagem , Piridazinas/síntese química , Ratos , Proteínas Recombinantes/agonistas , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
The identification of a series of imidazo[1,2-b][1,2,4]triazines with high affinity and functional selectivity for the GABA(A) alpha3-containing receptor subtype is described, leading to the identification of a clinical candidate, 11. Compound 11 shows good bioavailability and half-life in preclinical species, and it is a nonsedating anxiolytic in both rat and squirrel monkey behavioral models.
Assuntos
Ansiolíticos/síntese química , Agonistas de Receptores de GABA-A , Imidazóis/síntese química , Triazinas/síntese química , Animais , Ansiolíticos/química , Ansiolíticos/farmacologia , Disponibilidade Biológica , Meia-Vida , Humanos , Imidazóis/química , Imidazóis/farmacologia , Técnicas de Patch-Clamp , Ensaio Radioligante , Ratos , Receptores de GABA-A/fisiologia , Saimiri , Relação Estrutura-Atividade , Triazinas/química , Triazinas/farmacologiaRESUMO
Imidazo[1,2-a]pyrimidines and imidazo[1,2-b][1,2,4]triazines are ligands for the benzodiazepine binding site of GABA(A) receptors that are functionally selective for the alpha2/alpha3 subtypes over the alpha1 subtype. SAR studies to optimise this functional selectivity, pharmacokinetic and behavioural data are described.
Assuntos
Transtornos de Ansiedade/tratamento farmacológico , Agonistas de Receptores de GABA-A , Imidazóis/farmacologia , Subunidades Proteicas/agonistas , Triazinas/farmacologia , Administração Oral , Animais , Ataxia/tratamento farmacológico , Sítios de Ligação , Disponibilidade Biológica , Modelos Animais de Doenças , Cães , Feminino , Agonistas GABAérgicos/farmacocinética , Agonistas GABAérgicos/farmacologia , Imidazóis/farmacocinética , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Estrutura Molecular , Subunidades Proteicas/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de GABA-A/metabolismo , Saimiri , Relação Estrutura-Atividade , Triazinas/farmacocinéticaRESUMO
The GABA(A) receptor subtypes responsible for the anxiolytic effects of nonselective benzodiazepines (BZs) such as chlordiazepoxide (CDP) and diazepam remain controversial. Hence, molecular genetic data suggest that alpha2-rather than alpha3-containing GABA(A) receptors are responsible for the anxiolytic effects of diazepam, whereas the anxiogenic effects of an alpha3-selective inverse agonist suggest that an agonist selective for this subtype should be anxiolytic. We have extended this latter pharmacological approach to identify a compound, 4,2'-difluoro-5'-[8-fluoro-7-(1-hydroxy-1-methylethyl)imidazo[1,2-á]pyridin-3-yl]biphenyl-2-carbonitrile (TP003), that is an alpha3 subtype selective agonist that produced a robust anxiolytic-like effect in both rodent and non-human primate behavioral models of anxiety. Moreover, in mice containing a point mutation that renders alpha2-containing receptors BZ insensitive (alpha2H101R mice), TP003 as well as the nonselective agonist CDP retained efficacy in a stress-induced hyperthermia model. Together, these data show that potentiation of alpha3-containing GABA(A) receptors is sufficient to produce the anxiolytic effects of BZs and that alpha2 potentiation may not be necessary.
