ABSTRACT
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.
Subject(s)
Amino Acid Transport Systems, Neutral/antagonists & inhibitors , Glycine/analogs & derivatives , Glycine/pharmacology , Hippocampus/physiology , Inhibition, Psychological , Reflex, Startle/physiology , Animals , Animals, Newborn , Dose-Response Relationship, Drug , Glutamic Acid/metabolism , Glycine/metabolism , Glycine Plasma Membrane Transport Proteins , Hippocampus/drug effects , Ibotenic Acid , Rats , Rats, Sprague-Dawley , Receptors, N-Methyl-D-Aspartate/agonists , Receptors, N-Methyl-D-Aspartate/metabolism , Reflex, Startle/drug effectsABSTRACT
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.
Subject(s)
Excitatory Amino Acid Antagonists/chemistry , Imidazoles/chemistry , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Animals , Cells, Cultured , Excitatory Amino Acid Antagonists/administration & dosage , Excitatory Amino Acid Antagonists/pharmacology , Imidazoles/administration & dosage , Imidazoles/pharmacology , Injections, Intraperitoneal , Mice , Mice, Inbred DBA , Potassium Channels, Voltage-Gated/antagonists & inhibitors , Receptors, N-Methyl-D-Aspartate/physiology , Seizures/prevention & controlABSTRACT
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.
Subject(s)
Pyridines/chemical synthesis , Quinolines/chemical synthesis , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Animals , Mice , Pyridines/pharmacology , Quinolines/pharmacology , Seizures/drug therapy , Structure-Activity RelationshipABSTRACT
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.
