RESUMO
A series of N-propyl-8-chloro-6-substituted isoquinolones was identified as positive allosteric modulators of metabotropic glutamate receptor 2 (mGluR2 PAM) via high throughput screening (HTS). The subsequent synthesis and initial SAR exploration that led to the identification of compound 28 is described.
Assuntos
Piridinas/síntese química , Quinolonas/química , Receptores de Glutamato Metabotrópico/química , Regulação Alostérica , Ensaios de Triagem em Larga Escala , Humanos , Microssomos Hepáticos/metabolismo , Piridinas/química , Piridinas/farmacologia , Quinolonas/síntese química , Quinolonas/farmacologia , Receptores de Glutamato Metabotrópico/metabolismo , Relação Estrutura-AtividadeRESUMO
A series of 1,5-disubstituted pyridones was identified as positive allosteric modulators (PAMs) of the metabotropic glutamate receptor 2 (mGluR2) via high throughput screening (HTS). Subsequent SAR exploration led to the identification of several compounds with improved in vitro activity. Lead compound 8 was further profiled and found to attenuate the increase in PCP induced locomotor activity in mice.
Assuntos
Aminoácidos/farmacologia , Compostos Bicíclicos com Pontes/farmacologia , Agonistas de Aminoácidos Excitatórios/farmacologia , Piridinas/farmacologia , Piridonas/farmacologia , Receptores de Glutamato Metabotrópico/agonistas , Sulfonamidas/farmacologia , Regulação Alostérica , Aminoácidos/química , Animais , Compostos Bicíclicos com Pontes/química , Avaliação Pré-Clínica de Medicamentos , Estabilidade de Medicamentos , Agonistas de Aminoácidos Excitatórios/química , Agonistas de Aminoácidos Excitatórios/classificação , Humanos , Interações Hidrofóbicas e Hidrofílicas , Camundongos , Estrutura Molecular , Atividade Motora/efeitos dos fármacos , Piridinas/química , Piridonas/química , Piridonas/classificação , Piridonas/isolamento & purificação , Proteínas Recombinantes/efeitos dos fármacos , Relação Estrutura-Atividade , Sulfonamidas/químicaRESUMO
Compiling pharmacological evidence implicates metabotropic glutamate mGlu(2) receptors in the regulation of emotional states and suggests positive modulators as a novel therapeutic approach of Anxiety/Depression and Schizophrenia. Here, we investigated subcutaneous effects of the metabotropic glutamate mGlu(2/3) agonist (LY354740) on sleep-wake architecture in rat. To confirm the specific effects on rapid eye movement (REM) sleep were mediated via metabotropic glutamate mGlu(2) receptors, we characterized the sleep-wake cycles in metabotropic glutamate mGlu(2) receptor deficient mice (mGlu(2)R(-/-)) and their arousal response to LY354740. We furthermore examined effects on sleep behavior in rats of the positive allosteric modulator, biphenyl-indanone A (BINA) alone and in combination with LY354740 at sub-effective doses. LY354740 (1, 3 and 10 mg/kg) dose-dependently suppressed REM sleep and prolonged its onset latency. Metabotropic glutamate mGlu(2)R(-/-) and their wild type (WT) littermates exhibited similar spontaneous sleep-wake phenotype, while LY354740 (10 mg/kg) significantly affected REM sleep variables in WT but not in the mutant. In rats, BINA (1, 3, 10, 20, 40 mg/kg) dose-dependently suppressed REM sleep, lengthened its onset latency and slightly enhanced passive waking. Additionally, combined treatment elicited a synergistic action on REM sleep variables. Our findings show common changes of REM sleep variables following modulation of metabotropic glutamate mGlu(2) receptor and support an active role of this receptor in the regulation of REM sleep. The synergistic action of BINA on LY354740's effects on sleep pattern implies that positive modulators would tune the endogenous glutamate tone suggesting potential benefit in the treatment of psychiatric disorders, in which REM sleep overdrive is manifested.