RESUMO
BACKGROUND: Neonatal ventral hippocampal (NVH) lesions in rats induce behavioral abnormalities at adulthood thought to simulate some aspects of the positive, negative, and cognitive deficits classically observed in schizophrenic patients. Such lesions induce a postpubertal emergence of prepulse inhibition (PPI) deficits of the startle reflex reminiscent of the sensorimotor gating deficits observed in a majority of schizophrenic patients. To study the potential involvement of the glycinergic neurotransmission in such deficits, we investigated the capacity of glycine (an obligatory N-methyl-D-aspartate [NMDA] receptor co-agonist) and ORG 24598 (a selective glycine transporter 1 inhibitor) to reverse NVH lesion-induced PPI deficits in rats. METHODS: Ibotenic acid was injected bilaterally into the ventral hippocampus of 7-day-old pups. Prepulse inhibition of the startle reflex was measured at adulthood. RESULTS: Glycine (.8 and 1.6 g/kg IP) and ORG 24598 (10 mg/kg IP) fully and partially reversed lesion-induced PPI deficits, respectively. CONCLUSIONS: These findings confirm that an impaired glutamatergic neurotransmission may be responsible for PPI deficits exhibited by NVH-lesioned rats and support the hypoglutamatergic hypothesis of schizophrenia. They also suggest that drugs acting either directly at the NMDA receptor glycine site or indirectly on the glycine transporter 1 could offer promising targets for the development of novel therapies for schizophrenia.
Assuntos
Sistemas de Transporte de Aminoácidos Neutros/antagonistas & inibidores , Glicina/análogos & derivados , Glicina/farmacologia , Hipocampo/fisiologia , Inibição Psicológica , Reflexo de Sobressalto/fisiologia , Animais , Animais Recém-Nascidos , Relação Dose-Resposta a Droga , Ácido Glutâmico/metabolismo , Glicina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Glicina , Hipocampo/efeitos dos fármacos , Ácido Ibotênico , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/agonistas , Receptores de N-Metil-D-Aspartato/metabolismo , Reflexo de Sobressalto/efeitos dos fármacosRESUMO
Screening of the Roche compound depository led to the identification of (1-benzyloxy-4,5-dihydro-1H-imidazol-2-yl)-butyl amine 4, a structurally novel NR1/2B subtype selective NMDA receptor antagonist. The structure-activity relationships developed in this series resulted in the discovery of a novel class of potent and selective NMDA receptor blockers displaying activity in vivo.
Assuntos
Antagonistas de Aminoácidos Excitatórios/química , Imidazóis/química , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Animais , Células Cultivadas , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Antagonistas de Aminoácidos Excitatórios/farmacologia , Imidazóis/administração & dosagem , Imidazóis/farmacologia , Injeções Intraperitoneais , Camundongos , Camundongos Endogâmicos DBA , Canais de Potássio de Abertura Dependente da Tensão da Membrana/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/fisiologia , Convulsões/prevenção & controleRESUMO
A series of 4-(3,4-dihydro-1H-isoquinolin-2yl)-pyridines and analogous quinolines was prepared and evaluated as NR1/2B subtype selective NMDA receptor antagonists. 2-Hydroxyalkylamino substitution combines high affinity with selectivity (vs alpha1 and M1 receptors) and activity in vivo.
Assuntos
Piridinas/síntese química , Quinolinas/síntese química , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Animais , Camundongos , Piridinas/farmacologia , Quinolinas/farmacologia , Convulsões/tratamento farmacológico , Relação Estrutura-AtividadeRESUMO
Recently, we disclosed 4-aminoquinolines as structurally novel NR1/2B subtype selective NMDA receptor antagonists. We would now like to report our findings on structurally related pyridine analogues. The SAR developed in this series resulted in the discovery of high affinity antagonists which are selective (vs alpha1 and M1 receptors) and active in vivo.