A Novel Selective Positive Allosteric Modulator of Metabotropic Glutamate Receptor Subtype 5 Has in Vivo Activity and Antipsychotic-Like Effects in Rat Behavioral Models

Abstract

We found that 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB) is a potent and selective positive allosteric modulator of the metabotropic glutamate receptor subtype 5 (mGluR5). In Chinese hamster ovary cells expressing human mGluR5, CDPPB potentiated threshold responses to glutamate in fluorometric Ca 2ϩ assays more than 7-fold with an EC 50 value of approximately 27 nM. At 1 M, CDPPB shifted mGluR5 agonist concentration response curves to glutamate, quisqualate, and (R,S)-3,5-dihydroxyphenylglycine 3-to 9-fold to the left. At higher concentrations, CDPPB exhibited agonist-like activity on cells expressing mGluR5. No other activity was observed on any other mGluR or cell type at concentrations up to 10 M. CDPPB had no effect on [ 3 H]quisqualate binding to mGluR5 but did compete for binding of [ 3 H]methoxyPEPy, an analog of the selective mGluR5 negative allosteric modulator MPEP. CDPPB was found to be brain penetrant and reversed amphetamine-induced locomotor activity and amphetamineinduced deficits in prepulse inhibition in rats, two models sensitive to antipsychotic drug treatment. These results demonstrate that positive allosteric modulation of mGluR5 produces behavioral effects, suggesting that such modulation serves as a viable approach to increasing mGluR5 activity in vivo. These effects are consistent with the hypothesis that allosteric potentiation of mGluR5 may provide a novel approach for development of antipsychotic agents.Glutamate, the predominant excitatory neurotransmitter in the mammalian central nervous system (CNS), exerts its effects through two classes of receptors. The first class of receptor, ionotropic glutamate receptors, are postsynaptic, multimeric ligand-gated ion channels classified into three groups named for group-selective agonists: N-methyl-D-aspartate (NMDA), ␣-amino-3-hydroxy-5-methyl-4-isoxazopropionic acid, and kainate receptors. The NMDA receptor (NMDAR) is known to play an important role in processes related to schizophrenia. NMDAR antagonists, such as phencyclidine and ketamine, induce positive, negative, and cognitive symptoms reminiscent of schizophrenia in human volunteers and worsen existing symptoms in schizophrenic patients. This observation has led to the hypothesis that changes in CNS circuits induced by NMDAR hypofunction may play a key role in the development and/or in the underlying symptoms of schizophrenia (Olney et al., 1999). Therefore, development of compounds that selectively increase NMDAR function could be used to test this hypothesis.The metabotropic glutamate receptors (mGluRs), the second class of glutamate receptor, are members of family C of the G-protein-coupled receptors and are characterized by a large extracellular agonist binding domain on the aminoterminal end of the receptor that is distinct from the seventransmembrane domain characteristic of all G-protein-couArticle, publication date, and citation information can be found at

Progress toward Positive Allosteric Modulators of the Metabotropic Glutamate Receptor Subtype 5 (mGlu5)

“…26,45,46 In contrast to DFB, CDPPB was shown to be the first systemically available mGlu 5 PAM, thus allowing for behavioral assessment in antipsychotic models, including reversal of amphetamine induced hyperlocomotion and reversal of deficits in prepulse inhibition, both of which have translational validity in patients with schizophrenia eliciting positive symptoms and cognitive deficits in sensory motor gating, respectively. CDPPB was shown to be efficacious in both of these models at moderate subcutaneous (s.c.) doses between 10 and 30 mg/kg.…”

Positive Allosteric Modulation of Metabotropic Glutamate 5 (mGlu5) Receptors Reverses N-Methyl-D-Aspartate Antagonist-Induced Alteration of Neuronal Firing in Prefrontal Cortex

“…The MK801 (Sigma-RBI, St. Louis, Missouri) was dissolved in saline (.9% sodium chloride [NaCl]). The route of administration (IP) and doses of CDPPB (3 and 10 mg/kg) were chosen according to Kinney et al (2005a).…”

“…Conversely, the mGlu5 receptor antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP) potentiates the effects of NMDA receptor antagonists on spontaneous burst and spike activity of cortical neurons (Homayoun and Moghaddam 2006). Behavioral studies also show that MPEP enhances the effects of NMDA antagonist blockade on prepulse inhibition, locomotion, working memory, and instrumental learning impairments (Campbell et al 2004;Homayoun et al 2004;Kinney et al 2005a;Spooren et al 2000). The worsening of the detrimental effects of NMDA receptor antagonists by mGlu5 receptor antagonist suggests that activation of mGlu5 receptors may represent a plausible approach for ameliorating symptoms of schizophrenia (Marino and Conn 2002;Moghaddam 2004).…”

“…The worsening of the detrimental effects of NMDA receptor antagonists by mGlu5 receptor antagonist suggests that activation of mGlu5 receptors may represent a plausible approach for ameliorating symptoms of schizophrenia (Marino and Conn 2002;Moghaddam 2004). Recent behavioral studies using 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB), a positive allosteric modulator of the mGlu5 receptor (Kinney et al 2005b;O'Brien et al 2004), show that pretreatment with this compound reverses amphetamine-induced hyperlocomotion and prepulse inhibition deficit, two tests which serve to model some aspects of schizophrenia in rodents (Kinney et al 2005a). …”

Control of neuronal excitability by Group I metabotropic glutamate receptors

“…Binding of a negative allosteric modulator to this site results in non-competitive inhibition of the receptor. Positive allosteric modulators do not activate the receptor, but can change the EC50 for an orthosteric agonist or increase its maximum effect (Ellaithy et al 2015;Kinney et al 2005;Knoflach et al 2001;Layton 2005;Sengmany et al 2017). The history of mGlu receptor pharmacology and drug development, as well as comprehensive lists of disclosed compounds with orthosteric or allosteric activity, is well documented (Alexander et al 2011;Ferraguti et al 2008;Pin et al 1999;Schoepp et al 1999).…”