ABSTRACT
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
RATIONALE: Phosphodiesterases (PDEs) belonging to the PDE4 family control intracellular concentrations of cyclic adenosine monophosphate (cAMP) by catalyzing its hydrolysis. Four separate PDE4 genes (PDE4A, PDE4B, PDE4C, and PDE4D) have been identified. PDE4 has been reported to be involved in various central nervous system (CNS) functions including depression, memory, and schizophrenia, although the specific subtype mediating these effects remains unclear. OBJECTIVE: To investigate the role of PDE4B in the CNS, PDE4B wild-type and knockout mice (C57BL/6N background) were assessed in a variety of well-characterized behavioral tasks, and their brains were assayed for monoamine content. RESULTS: Knockout mice showed a significant reduction in prepulse inhibition. Spontaneous locomotor activity was decreased (16%) in knockout mice. Furthermore, when challenged with amphetamine, both groups of mice responded similarly to a low dose of d-amphetamine (1.0 mg/kg), but knockout mice showed an enhanced response to a higher dose (1.78 mg/kg). Decreases in baseline levels of monoamines and their metabolites within the striatum of knockout mice were also observed. PDE4B knockout mice showed a modest decrease in immobility time in the forced swim test that approached significance. In several other tests, including the elevated plus maze, hot plate, passive avoidance, and Morris water maze, wild-type and knockout mice performed similarly. CONCLUSION: The present studies demonstrate decreased striatal DA and 5-HT activity in the PDE4B knockout mice associated with decreased prepulse inhibition, decreased baseline motor activity, and an exaggerated locomotor response to amphetamine. These data further support a role for PDE4B in psychiatric diseases and striatal function.
Subject(s)
Behavior, Animal/physiology , Brain/physiopathology , Cyclic Nucleotide Phosphodiesterases, Type 4/genetics , Dopamine/metabolism , Serotonin/metabolism , Animals , Arousal/drug effects , Arousal/physiology , Behavior, Animal/drug effects , Brain/drug effects , Dextroamphetamine/pharmacology , Dose-Response Relationship, Drug , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Motivation , Motor Activity/drug effects , Motor Activity/physiology , Reflex, Startle/drug effects , Reflex, Startle/physiologyABSTRACT
The phenotype of genetically modified animals is strongly influenced by both the genetic background of the animal as well as environmental factors. We have previously reported the behavioral and neurochemical characterization of PDE10A knockout mice maintained on a DBA1LacJ (PDE10A(DBA)) genetic background. The aim of the present studies was to assess the behavioral and neurochemical phenotype of PDE10A knockout mice on an alternative congenic C57BL/6N (PDE10A(C57)) genetic background. Consistent with our previous results, PDE10A(C57) knockout mice showed a decrease in exploratory locomotor activity and a delay in the acquisition of conditioned avoidance responding. Also consistent with previous studies, the elimination of PDE10A did not alter basal levels of striatal cGMP or cAMP or affect behavior in several other well-characterized behavioral assays. PDE10A(C57) knockout mice showed a blunted response to MK-801, although to a lesser degree than previously observed in the PDE10A(DBA) knockout mice, and no differences were observed following a PCP challenge. PDE10A(C57) knockout mice showed a significant change in striatal dopamine turnover, which was accompanied by an enhanced locomotor response to AMPH, These studies demonstrate that while many of the behavioral effects of the PDE10A gene deletion appear to be independent of genetic background, the impact of the deletion on behavior can vary in magnitude. Furthermore, the effects on the dopaminergic system appear to be background-dependent, with significant effects observed only in knockout mice on the C57BL6N genetic background.
Subject(s)
Behavior, Animal/physiology , Phosphoric Diester Hydrolases/genetics , Phosphoric Diester Hydrolases/physiology , Amphetamine/pharmacology , Animals , Anxiety/psychology , Avoidance Learning/drug effects , Avoidance Learning/physiology , Behavior, Animal/drug effects , Biogenic Monoamines/metabolism , Brain Chemistry/drug effects , Brain Chemistry/genetics , Chromatography, High Pressure Liquid , Depression/psychology , Dizocilpine Maleate/pharmacology , Dopamine/metabolism , Dopamine Uptake Inhibitors/pharmacology , Excitatory Amino Acid Antagonists/pharmacology , Hot Temperature , Methamphetamine/pharmacology , Mice , Mice, Inbred C57BL , Mice, Knockout , Motor Activity/drug effects , Nucleotides, Cyclic/metabolism , Pain Measurement/drug effects , Phencyclidine/pharmacology , Phosphoproteins/metabolism , Serotonin/metabolism , Swimming/psychologyABSTRACT
RATIONALE: The structurally related neuropeptides, substance P, neurokinin A, and neurokinin B, belong to a family of molecules termed tachykinins and are widely distributed in the central and peripheral nervous systems. These peptides mediate their effects through three G protein coupled receptor subtypes, the neurokinin-1, neurokinin-2 and neurokinin-3 receptors, respectively. OBJECTIVE: To study the physiological functions of NK3, a line of NK3 knockout mice were generated and characterized in a broad spectrum of well-established behavioral tests. RESULTS: In several tests, including spontaneous locomotor activity, elevated plus maze, forced swim, and hot plate, wild-type and knockout mice performed similarly. However, in several cognition tests, including passive avoidance, acquisition of conditioned avoidance responding (CAR), and the Morris water maze, NK3 knockout mice displayed deficits compared to wild-type mice. Although NK3 wild-type and knockout mice performed similarly in the training phase of the passive avoidance test, knockout mice had shorter latencies to enter the dark compartment on days 3 and 4, suggesting impaired retention. In the acquisition phase of the conditioned avoidance responding assay, NK3 knockout mice acquired the CAR task at a slower rate than wild-type mice. Once the CAR test was acquired, both NK3 wild-type and knockout mice responded similarly to clozapine and risperidone, drugs which suppress responding in this test. In the Morris water maze, NK3 knockout mice showed increased latencies to find the escape platform on day 3 of training, suggesting a modest, but significant delay in acquisition compared to wild-type mice. CONCLUSION: These studies suggest a role for NK3 in learning and memory in mice.
Subject(s)
Avoidance Learning/physiology , Cognition Disorders/physiopathology , Motor Activity/physiology , Receptors, Neurokinin-3/physiology , Age Factors , Animals , Antipsychotic Agents/pharmacology , Avoidance Learning/drug effects , Behavior, Animal/drug effects , Clozapine/pharmacology , Conditioning, Operant/drug effects , Dose-Response Relationship, Drug , Electric Stimulation , Gene Expression , Male , Maze Learning/drug effects , Mice , Mice, Inbred C57BL , Mice, Knockout , Motor Activity/drug effects , Receptors, Neurokinin-3/deficiency , Receptors, Neurokinin-3/genetics , Reverse Transcriptase Polymerase Chain Reaction , Risperidone/pharmacology , Swimming , Time Factors , Weight Gain/drug effectsABSTRACT
RATIONALE: Recent studies provide evidence for reduced phosphodiesterase-4B (PDE4B) as a genetic susceptibility factor as well as suggesting an association of several single nucleotide polymorphisms (SNPs) in PDE4B that are associated with an increased incidence of schizophrenia. OBJECTIVES: The aim of the current study was to assess the activity of rolipram, a nonsubtype-selective PDE4 inhibitor, in several animal models predictive of antipsychotic-like efficacy and side-effect liability and to use PDE4B wild-type and knockout mice to begin to understand the subtypes involved in the activity of rolipram. RESULTS: In rats, rolipram antagonized both phencyclidine hydrochloride- and D-amphetamine-induced hyperactivity and inhibited conditioned avoidance responding (CAR). In PDE4B wild-type mice, rolipram dose-dependently suppressed CAR (ED(50) = 2.4 mg/kg); however, in knockout mice, their sensitivity to rolipram at the higher doses (1.0 and 3.2 mg/kg) was reduced, resulting in a threefold shift in the ED(50) (7.3 mg/kg), suggesting PDE4B is involved, at least in part, with the activity of rolipram. Only the highest dose of rolipram (3.2 mg/kg) produced a modest but significant degree of catalepsy. CONCLUSIONS: Rolipram has a pharmacologic profile similar to that of the atypical antipsychotics and has low extrapyramidal symptom liability. These results suggest that PDE4B mediates the antipsychotic effects of rolipram in CAR and that the PDE4B-regulated cyclic adenosine monophosphate signaling pathway may play a role in the pathophysiology and pharmacotherapy of psychosis.
Subject(s)
3',5'-Cyclic-AMP Phosphodiesterases/genetics , Antipsychotic Agents/pharmacology , Behavior, Animal/drug effects , Rolipram/pharmacology , 3',5'-Cyclic-AMP Phosphodiesterases/metabolism , Animals , Antipsychotic Agents/administration & dosage , Antipsychotic Agents/adverse effects , Avoidance Learning/drug effects , Catalepsy/chemically induced , Conditioning, Operant/drug effects , Cyclic AMP/metabolism , Cyclic Nucleotide Phosphodiesterases, Type 4 , Disease Models, Animal , Dose-Response Relationship, Drug , Hyperkinesis/chemically induced , Hyperkinesis/drug therapy , Male , Mice , Mice, Inbred DBA , Mice, Knockout , Motor Activity/drug effects , Polymorphism, Genetic , Psychotic Disorders/drug therapy , Psychotic Disorders/physiopathology , Rats , Rolipram/administration & dosage , Rolipram/adverse effects , Schizophrenia/drug therapy , Schizophrenia/physiopathology , Signal TransductionABSTRACT
CP-809,101 is a potent, functionally selective 5-HT(2C) agonist that displays approximately 100% efficacy in vitro. The aim of the present studies was to assess the efficacy of a selective 5-HT(2C) agonist in animal models predictive of antipsychotic-like efficacy and side-effect liability. Similar to currently available antipsychotic drugs, CP-809,101 dose-dependently inhibited conditioned avoidance responding (CAR, ED(50)=4.8 mg/kg, sc). The efficacy of CP-809,101 in CAR was completely antagonized by the concurrent administration of the 5-HT(2C) receptor antagonist, SB-224,282. CP-809,101 antagonized both PCP- and d-amphetamine-induced hyperactivity with ED(50) values of 2.4 and 2.9 mg/kg (sc), respectively and also reversed an apomorphine induced-deficit in prepulse inhibition. At doses up to 56 mg/kg, CP-809,101 did not produce catalepsy. Thus, the present results demonstrate that the 5-HT(2C) agonist, CP-809,101, has a pharmacological profile similar to that of the atypical antipsychotics with low extrapyramidal symptom liability. CP-809,101 was inactive in two animal models of antidepressant-like activity, the forced swim test and learned helplessness. However, CP-809,101 was active in novel object recognition, an animal model of cognitive function. These data suggest that 5-HT(2C) agonists may be a novel approach in the treatment of psychosis as well as for the improvement of cognitive dysfunction associated with schizophrenia.
Subject(s)
Antipsychotic Agents/therapeutic use , Psychotic Disorders/drug therapy , Serotonin 5-HT2 Receptor Agonists , Serotonin Receptor Agonists/therapeutic use , Amphetamines , Animals , Antipsychotic Agents/chemistry , Avoidance Learning/drug effects , Behavior, Animal , Catalepsy/chemically induced , Catalepsy/drug therapy , Dextroamphetamine , Disease Models, Animal , Dose-Response Relationship, Drug , Exploratory Behavior/drug effects , Helplessness, Learned , Humans , Hyperkinesis/chemically induced , Hyperkinesis/drug therapy , Inhibition, Psychological , Male , Mice , Motor Activity/drug effects , NIH 3T3 Cells , Piperazines/chemistry , Piperazines/therapeutic use , Protein Binding/drug effects , Psychotic Disorders/etiology , Psychotic Disorders/physiopathology , Pyrazines/chemistry , Pyrazines/therapeutic use , Rats , Rats, Wistar , Receptor, Serotonin, 5-HT2C/physiologyABSTRACT
Phosphodiesterase 10A (PDE10A) is a recently identified cyclic nucleotide phosphodiesterase expressed primarily in dopaminoreceptive medium spiny neurons of the striatum. We report that papaverine is a potent, specific inhibitor of PDE10A and use this compound to explore the role of PDE10A in regulating striatal function. Papaverine administration produces an increase in striatal tissue levels of cGMP and an increase in extracellular cAMP measured by microdialysis. These cyclic nucleotide changes are accompanied by increases in the phosphorylation of CREB and ERK, downstream markers of neuronal activation. In rats, papaverine potentiates haloperidol-induced catalepsy, consistent with the hypothesis that inhibition of PDE10A can increase striatal output and prompting a further evaluation of papaverine in models predictive of antipsychotic activity. Papaverine is found to inhibit conditioned avoidance responding in rats and mice and to inhibit PCP- and amphetamine-stimulated locomotor activity in rats. The effects of papaverine on striatal cGMP and CREB and ERK phosphorylation, as well as on conditioned avoidance responding, were absent in PDE10A knockout mice, indicating that the effects of the compound are the result of PDE10A inhibition. These results indicate that PDE10A regulates the activation of striatal medium spiny neurons through effects on cAMP- and cGMP-dependent signaling cascades. Furthermore, the present results demonstrate that papaverine has efficacy in behavioral models predictive of antipsychotic activity. Thus, inhibition of PDE10A may represent a novel approach to the treatment of psychosis.
Subject(s)
Antipsychotic Agents/pharmacology , Corpus Striatum/enzymology , Papaverine/pharmacology , Phosphodiesterase Inhibitors/pharmacology , Phosphoric Diester Hydrolases/physiology , Animals , Avoidance Learning/drug effects , Catalepsy/chemically induced , Central Nervous System Stimulants/pharmacology , Corpus Striatum/metabolism , Cyclic AMP/metabolism , Cyclic AMP Response Element-Binding Protein/metabolism , Cyclic GMP/metabolism , Dendritic Spines/drug effects , Dendritic Spines/physiology , Dextroamphetamine/pharmacology , Drug Synergism , Excitatory Amino Acid Antagonists/pharmacology , Extracellular Signal-Regulated MAP Kinases/metabolism , Haloperidol/pharmacology , Mice , Mice, Knockout , Motor Activity/drug effects , Phencyclidine/pharmacology , Phosphorylation , RatsABSTRACT
PDE10A is a newly identified phosphodiesterase that is highly expressed by the medium spiny projection neurons of the striatum. In order to investigate the physiological role of PDE10A in the central nervous system, PDE10A knockout mice (PDE10A(-/-)) were characterized both behaviorally and neurochemically. PDE10A(-/-) mice showed decreased exploratory activity and a significant delay in the acquisition of conditioned avoidance behavior when compared to wild-type (PDE10A(+/+)) mice. However, in a variety of other well-characterized behavioral tasks, including the elevated plus maze (anxiety), forced swim test (depression), hot plate (nociception) and two memory models (passive avoidance and Morris water maze), PDE10A(-/-) mice performed similarly to wild-type mice. When challenged with PCP or MK-801, PDE10A(-/-) mice showed a blunted locomotor response in comparison to PDE10A(+/+) mice. In contrast, PDE10A(-/-) and PDE10A(+/+) mice responded similarly to the locomotor stimulating effects of amphetamine and methamphetamine. Our findings suggest that PDE10A is involved in regulating striatal output, possibly by reducing the sensitivity of medium spiny neurons to glutamatergic excitation. These results are discussed in relationship to the hypothesis that PDE10A inhibition presents a novel treatment for psychosis.
