ABSTRACT
Observations that N-Methyl-D-Aspartate (NMDA) antagonists produce symptoms in humans that are similar to those seen in schizophrenia have led to the current hypothesis that schizophrenia might result from NMDA receptor hypofunction. Inhibition of D-amino acid oxidase (DAAO), the enzyme responsible for degradation of D-serine, should lead to increased levels of this co-agonist at the NMDA receptor, and thereby provide a therapeutic approach to schizophrenia. We have profiled some of the preclinical biochemical, electrophysiological, and behavioral consequences of administering potent and selective inhibitors of DAAO to rodents to begin to test this hypothesis. Inhibition of DAAO activity resulted in a significant dose and time dependent increase in D-serine only in the cerebellum, although a time delay was observed between peak plasma or brain drug concentration and cerebellum D-serine response. Pharmacokinetic/pharmacodynamic (PK/PD) modeling employing a mechanism-based indirect response model was used to characterize the correlation between free brain drug concentration and D-serine accumulation. DAAO inhibitors had little or no activity in rodent models considered predictive for antipsychotic activity. The inhibitors did, however, affect cortical activity in the Mescaline-Induced Scratching model, produced a modest but significant increase in NMDA receptor-mediated synaptic currents in primary neuronal cultures from rat hippocampus, and resulted in a significant increase in evoked hippocampal theta rhythm, an in vivo electrophysiological model of hippocampal activity. These findings demonstrate that although DAAO inhibition did not cause a measurable increase in D-serine in forebrain, it did affect hippocampal and cortical activity, possibly through augmentation of NMDA receptor-mediated currents.
Subject(s)
Brain/metabolism , D-Amino-Acid Oxidase/antagonists & inhibitors , Memory, Short-Term/physiology , Psychomotor Agitation/drug therapy , Receptors, N-Methyl-D-Aspartate/metabolism , Animals , Brain/drug effects , Central Nervous System Stimulants/metabolism , Central Nervous System Stimulants/pharmacology , Cyclic GMP/analysis , Cyclic GMP/biosynthesis , D-Amino-Acid Oxidase/metabolism , D-Amino-Acid Oxidase/physiology , Drug Evaluation, Preclinical , Electroencephalography , Habituation, Psychophysiologic/drug effects , Habituation, Psychophysiologic/physiology , Harmaline/metabolism , Hippocampus/drug effects , Hippocampus/metabolism , Male , Maze Learning/drug effects , Maze Learning/physiology , Memory, Short-Term/drug effects , Mescaline/pharmacology , Mice , Miniature Postsynaptic Potentials/drug effects , Miniature Postsynaptic Potentials/physiology , Models, Biological , Models, Chemical , Molecular Targeted Therapy , Motor Activity/drug effects , Motor Activity/physiology , Pruritus/chemically induced , Pruritus/prevention & control , Rats , Rats, Long-Evans , Rats, Sprague-Dawley , Receptors, N-Methyl-D-Aspartate/drug effects , Sensory Gating/drug effects , Sensory Gating/physiology , Serine/blood , Serotonin Receptor Agonists/pharmacologyABSTRACT
A novel series of mGluR2 positive allosteric modulators (PAMs), 1-[(1-methyl-1H-imidazol-2-yl)methyl]-4-phenylpiperidines, is herein disclosed. Structure-activity relationship studies led to potent, selective mGluR2 PAMs with excellent pharmacokinetic profiles. A representative lead compound (+)-17e demonstrated dose-dependent inhibition of methamphetamine-induced hyperactivity and mescaline-induced scratching in mice, providing support for potential efficacy in treating psychosis.
Subject(s)
Antipsychotic Agents/chemical synthesis , Bridged Bicyclo Compounds, Heterocyclic/chemical synthesis , Imidazoles/chemical synthesis , Piperidines/chemical synthesis , Receptors, Metabotropic Glutamate/metabolism , Allosteric Regulation , Animals , Antipsychotic Agents/pharmacokinetics , Antipsychotic Agents/pharmacology , Biological Availability , Brain/metabolism , Bridged Bicyclo Compounds, Heterocyclic/pharmacokinetics , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Cell Line , Dogs , Humans , Hyperkinesis/chemically induced , Hyperkinesis/drug therapy , Imidazoles/pharmacokinetics , Imidazoles/pharmacology , In Vitro Techniques , Methamphetamine , Mice , Microsomes, Liver/metabolism , Models, Molecular , Piperidines/pharmacokinetics , Piperidines/pharmacology , Protein Conformation , Radioligand Assay , Rats , Stereoisomerism , Structure-Activity RelationshipABSTRACT
The discovery, synthesis and SAR of a novel series of 3-benzyl-1,3-oxazolidin-2-ones as positive allosteric modulators (PAMs) of mGluR2 is described. Expedient hit-to-lead work on a single HTS hit led to the identification of a ligand-efficient and structurally attractive series of mGluR2 PAMs. Human microsomal clearance and suboptimal physicochemical properties of the initial lead were improved to give potent, metabolically stable and orally available mGluR2 PAMs.
Subject(s)
Carbamates/chemistry , Oxazolidinones/chemical synthesis , Receptors, Metabotropic Glutamate/antagonists & inhibitors , Receptors, Metabotropic Glutamate/chemistry , Schizophrenia/drug therapy , Administration, Oral , Allosteric Regulation , Allosteric Site , Chemistry, Pharmaceutical/methods , Drug Design , Humans , Inhibitory Concentration 50 , Ligands , Microsomes/metabolism , Models, Chemical , Molecular Structure , Oxazolidinones/chemistryABSTRACT
The synthesis and structure-activity relationship (SAR) of a novel series of 3-(imidazolyl methyl)-3-aza-bicyclo[3.1.0]hexan-6-yl)methyl ethers, derived from a high throughput screening (HTS), are described. Subsequent optimization led to identification of potent, metabolically stable and orally available mGluR2 positive allosteric modulators (PAMs).
Subject(s)
Allosteric Regulation , Azabicyclo Compounds/chemical synthesis , Benzimidazoles/chemical synthesis , Chemistry, Pharmaceutical/methods , Ethers/chemistry , Receptors, Metabotropic Glutamate/chemistry , Administration, Oral , Allosteric Site , Animals , Azabicyclo Compounds/pharmacology , Benzimidazoles/pharmacology , Drug Design , Drug Evaluation, Preclinical , Humans , Microsomes/drug effects , Models, Chemical , Rats , Schizophrenia/drug therapy , Structure-Activity RelationshipABSTRACT
BACKGROUND AND PURPOSE: Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor inhibition has been hypothesized to provide neuroprotective efficacy after cerebral ischemia on the basis of the activity in experimental ischemia models of a variety of compounds with varying selectivity for AMPA over other glutamate receptor subtypes. CP-465,022 is a new, potent, and selective noncompetitive AMPA receptor antagonist. The present study investigated the ability of this compound to reduce neuronal loss after experimental cerebral ischemia to probe the neuroprotective potential of AMPA receptor inhibition. METHODS: To demonstrate that CP-465,022 gains access to the brain, the effects of systemic administration of CP-465,022 were investigated on AMPA receptor-mediated electrophysiological responses in hippocampus and on chemically induced seizures in rats. The compound was then investigated for neuroprotective efficacy in rat global and focal ischemia models at doses demonstrated to be maximally effective in the electrophysiology and seizure models. RESULTS: CP-465,022 potently and efficaciously inhibited AMPA receptor-mediated hippocampal synaptic transmission and the induction of seizures. However, at comparable doses, CP-465,022 failed to prevent CA1 neuron loss after brief global ischemia or to reduce infarct volume after temporary middle cerebral artery occlusion. CONCLUSIONS: Given the high selectivity of CP-465,022 for AMPA over kainate and N-methyl-D-aspartate subtypes of glutamate receptors, the lack of neuroprotective efficacy of the compound calls into question the neuroprotective efficacy of AMPA receptor inhibition after ischemia.
