3-cyano-n-(1-3-diphenyl-1h-pyrazol-5-yl)benzamide and Schizophrenia

This article describes recent progress towards validation of the N-methyl-D-aspartate (NMDA) receptor hypofunction hypothesis of schizophrenia in preclinical models. Schizophrenia, a complex disease characterized by positive, negative and cognitive symptoms, affects 1% of the world population and requires lifelong, daily maintenance therapy. For the last several decades, thinking in this field has been dominated by the hypothesis that hyperfunction of dopamine pathways played a key role in schizophrenia. However, the therapeutic agents developed from this hypothesis have a slow onset of action and tend to improve only the positive symptoms of the disease. The NMDA receptor antagonist PCP has been shown to induce the positive, negative and cognitive symptoms of schizophrenia in healthy patients and cause a resurgence of symptoms in stable patients. These observations led to the NMDA receptor hypofunction hypothesis as an alternative theory for the underlying cause of schizophrenia. According to this hypothesis, any agent that can potentiate NMDA receptor currents has the potential to ameliorate the symptoms of schizophrenia. To date, NMDA receptor currents can be modulated by either direct action on modulatory sites on the NMDA receptor (i.e., the glycine co-agonist binding site) or indirectly by activation of G-protein coupled receptors (GPCRs) known to potentiate NMDA receptor function (i.e., mGluR5). This review will discuss the NMDA receptor hypofunction hypothesis, the NMDA receptor as an emerging target for the development of novel antipsychotic agents and progress towards in vivo target validation with GlyT1 inhibitors and mGluR5 positive allosteric modulators. Other potential targets for modulating NMDA receptor currents (polyamine sites, muscarinic receptors, etc...) will also be addressed briefly.

Topics: Allosteric Regulation; Animals; Antipsychotic Agents; Benzamides; Benzimidazoles; Brain; Glycine; Glycine Plasma Membrane Transport Proteins; Humans; Phthalimides; Pyrazoles; Receptor, Metabotropic Glutamate 5; Receptors, Metabotropic Glutamate; Receptors, N-Methyl-D-Aspartate; Sarcosine; Schizophrenia; Synaptic Transmission

This study was undertaken to examine the effects of CDPPB (3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide), a positive allosteric modulator (PAM) of metabotropic glutamate receptor 5 (mGlu₅), on cognitive deficits in mice after repeated administration of the N-methyl-D-aspartate (NMDA) receptor antagonist phencyclidine (PCP). In the novel object recognition test, PCP (10 mg/kg/day for 10 days)-induced cognitive deficits in mice were not improved by a single administration of CDPPB (10 mg/kg/day). However, PCP (10 mg/kg/day for 10 days)-induced cognitive deficits in mice were significantly improved by subsequent subchronic (14 days) administration of CDPPB (10 mg/kg/day), but not of CDPPB (1.0 mg/kg/day). This study suggests that PCP-induced cognitive deficits in mice are improved by subsequent subchronic administration of CDPPB. Therefore, mGlu₅ PAMs would be potential therapeutic drugs for cognitive deficits in schizophrenia.

Topics: Allosteric Regulation; Animals; Antipsychotic Agents; Behavior, Animal; Benzamides; Brain; Cognition Disorders; Disease Models, Animal; Dose-Response Relationship, Drug; Excitatory Amino Acid Agonists; Exploratory Behavior; Male; Mice; Mice, Inbred ICR; Nerve Tissue Proteins; Neurons; Phencyclidine; Pyrazoles; Receptor, Metabotropic Glutamate 5; Recognition, Psychology; Schizophrenia

Metabotropic glutamate-5 receptors (mGluR5), which physically and functionally interact with N-methyl-D-Aspartate (NMDA) receptors, likewise control cognitive processes and have been proposed as targets for novel classes of antipsychotic agent. Since social cognition is impaired in schizophrenia and disrupted by NMDA receptor antagonists like dizocilpine, we evaluated its potential modulation by mGluR5. Acute administration (0.63-40 mg/kg) of the mGluR5 positive allosteric modulators (PAMs), 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB) and ADX47273, reversed a delay-induced impairment in social novelty discrimination (SND) in adult rats. The action of CDPPB was blocked by the mGluR5 antagonist, 2-methyl-6-(phenylethynyl)-pyridine (2.5-10 mg/kg), and was also expressed upon microinjection into frontal cortex (0.63-10 μg/side), but not striatum. Supporting an interrelationship between mGluR5 and NMDA receptors, enhancement of SND by CDPPB was blocked by dizocilpine (0.08 mg/kg) while, reciprocally, dizocilpine-induced impairment in SND was attenuated by CDPPB (10 mg/kg). The SND deficit elicited by post-natal administration of phencyclidine (10 mg/kg, days 7-11) was reversed by CDPPB or ADX47273 in adults at week 8. This phencyclidine-induced impairment in cognition emerged in adult rats from week 7 on, and chronic, pre-symptomatic treatment of adolescent rats with CDPPB over weeks 5-6 (10 mg/kg per day) prevented the appearance of SND deficits in adults until at least week 13. In conclusion, as evaluated by a SND procedure, mGluR5 PAMs promote social cognition via actions expressed in interaction with NMDA receptors and exerted in frontal cortex. MGluR5 PAMs not only reverse but also (when given during adolescence) prevent the emergence of cognitive impairment associated with a developmental model of schizophrenia.

Topics: Aging; Allosteric Regulation; Animals; Animals, Newborn; Behavior, Animal; Benzamides; Brain; Discrimination, Psychological; Dizocilpine Maleate; Dose-Response Relationship, Drug; Male; Microinjections; Oxadiazoles; Phencyclidine; Piperidines; Pyrazoles; Rats; Rats, Wistar; Receptor, Metabotropic Glutamate 5; Receptors, Metabotropic Glutamate; Receptors, N-Methyl-D-Aspartate; Schizophrenia; Social Behavior

Positive allosteric modulation of metabotropic glutamate receptor 5 (mGluR5) is regarded as a potential novel treatment for schizophrenic patients. Herein we report the synthesis and SAR of 4-aryl piperazine and piperidine amides as potent mGluR5 positive allosteric modulators (PAMs). Several analogs have excellent activity and desired drug-like properties. Compound 2b was further characterized as a PAM using several in vitro experiments, and produced robust activity in several preclinical animal models.

Topics: Allosteric Regulation; Amides; Humans; Microsomes, Liver; Piperazine; Piperazines; Piperidines; Receptor, Metabotropic Glutamate 5; Receptors, Metabotropic Glutamate; Schizophrenia; Structure-Activity Relationship

Currently prescribed antipsychotics attenuate the positive symptoms of schizophrenia but fail or only mildly improve negative symptoms. The present study aimed to establish an animal model of negative symptoms by examining the effects of the NMDA receptor antagonist MK-801 on sucrose preference. We sought to validate the model by examining the effects of clozapine and D-serine, for which there are positive clinical data regarding their effects on negative symptoms, and haloperidol which is clinically ineffective. We extended our analysis by examining CDPPB, an mGlu5 receptor positive allosteric modulator. Acute MK-801 produced effects indicative of a shift in the hedonic experience of sucrose not confounded by disruptions in motor abilities or taste as revealed by: 1) a decrease in sucrose intake at low concentrations (0.8% or 1.2%), but no effect on water, 2) an increase in consumption for higher (7%) sucrose concentrations, reflecting a shift to the right in the concentration-consumption curve, and 3) no effect on quinine intake. Sub-chronic clozapine and acute d-serine attenuated the MK-801-induced deficit in 1.2% sucrose consumption, whereas sub-chronic haloperidol (0.02 mg/kg) did not. Finally, acute treatment with CDPPB also attenuated this deficit. These data suggest that this model may be useful for identifying novel agents that improve negative symptoms, and that compounds which enhance NMDA receptor function, such as mGlu5 receptor PAMs, may have clinical utility in this regard.

Topics: Allosteric Regulation; Animals; Benzamides; Clozapine; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Male; Pyrazoles; Quinine; Rats; Rats, Wistar; Receptor, Metabotropic Glutamate 5; Receptors, Metabotropic Glutamate; Schizophrenia; Serine; Sucrose

Metabotropic glutamate (mGlu) receptors provide a mechanism by which the function of NMDA glutamate receptors can be modulated. As NMDA receptor hypofunction is implicated in the etiology of psychiatric disorders, including schizophrenia, the pharmacological regulation of mGlu receptor activity represents a promising therapeutic approach. We examined the effects of the positive allosteric mGlu(5) receptor modulator 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB), alone and in combination with the NMDA receptor antagonist MK-801, on a task measuring cognitive set-shifting ability. This task measures NMDA receptor-dependent cognitive abilities analogous to those impaired in schizophrenia. Systemic administration of CDPPB (10 and 30 mg/kg i.p) blocked MK-801 (0.1mg/kg, i.p.)-induced impairments in set-shifting ability. The effect on learning was dose-dependent, with the 30 mg/kg dose having a greater effect than the 10mg/kg dose across all trials. This ameliorative effect of CDPPB reflected a reduction in MK-801-induced perseverative responding. These results add to the evidence that mGlu(5) receptors interact functionally with NMDA receptors to regulate behavior, and suggest that positive modulators of mGlu(5) receptors may have therapeutic potential in the treatment of disorders, like schizophrenia, characterized by impairments in cognitive flexibility and memory.

Topics: Allosteric Regulation; Animals; Benzamides; Cognition; Cognition Disorders; Dizocilpine Maleate; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Learning; Male; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Metabotropic Glutamate 5; Receptors, Metabotropic Glutamate; Receptors, N-Methyl-D-Aspartate; Schizophrenia