Partial mGlu5 Negative Allosteric Modulators Attenuate Cocaine-Mediated Behaviors and Lack Psychotomimetic-Like Effects

Abstract

Cocaine abuse remains a public health concern for which pharmacotherapies are largely ineffective. Comorbidities between cocaine abuse, depression, and anxiety support the development of novel treatments targeting multiple symptom clusters. Selective negative allosteric modulators (NAMs) targeting the metabotropic glutamate receptor 5 (mGlu 5 ) subtype are currently in clinical trials for the treatment of multiple neuropsychiatric disorders and have shown promise in preclinical models of substance abuse. However, complete blockade or inverse agonist activity by some full mGlu 5 NAM chemotypes demonstrated adverse effects, including psychosis in humans and psychotomimetic-like effects in animals, suggesting a narrow therapeutic window. Development of partial mGlu 5 NAMs, characterized by their submaximal but saturable levels of blockade, may represent a novel approach to broaden the therapeutic window. To understand potential therapeutic vs adverse effects in preclinical behavioral assays, we examined the partial mGlu 5 NAMs, M-5MPEP and Br-5MPEPy, in comparison with the full mGlu 5 NAM MTEP across models of addiction and psychotomimetic-like activity. M-5MPEP, Br-5MPEPy, and MTEP dose-dependently decreased cocaine self-administration and attenuated the discriminative stimulus effects of cocaine. M-5MPEP and Br-5MPEPy also demonstrated antidepressant-and anxiolytic-like activity. Dose-dependent effects of partial and full mGlu 5 NAMs in these assays corresponded with increasing in vivo mGlu 5 occupancy, demonstrating an orderly occupancy-to-efficacy relationship. PCP-induced hyperlocomotion was potentiated by MTEP, but not by M-5MPEP and Br-5MPEPy. Further, MTEP, but not M-5MPEP, potentiated the discriminative-stimulus effects of PCP. The present data suggest that partial mGlu 5 NAM activity is sufficient to produce therapeutic effects similar to full mGlu 5 NAMs, but with a broader therapeutic index.

Practical Strategies and Concepts in GPCR Allosteric Modulator Discovery: Recent Advances with Metabotropic Glutamate Receptors

“…PCP-induced hyperlocomotion, as well as the discriminative-stimulus effects of PCP, was potentiated by MTEP ( 76 ), but not by M-5MPEP ( 77 ) and Br-5MPEPy ( 78 ). 312 More recently, VU0477573 was reported as another partial NAM within this series that has higher affinity than the earlier partial NAMs, an excellent PK profile, and efficacy in rodent models of anxiolytic activity. 313 Thus, data are accumulating that demonstrate that efficacy with partial mGlu 5 NAM activity is comparable to that observed with full NAM activity but with a broader therapeutic index.…”

“…33–35,311 To understand potential therapeutic versus adverse effects in preclinical behavioral assays, the activities of the partial mGlu 5 NAMs M-5MPEP ( 77 ), Br-5MPEPy ( 78 ), and VU0477573 ( 79 ), in comparison with the full mGlu 5 NAM MTEP ( 76 ), were examined across models of addiction and psychotomimetic-like activity (Figure 23). 312,313 M-5MPEP ( 77 ), Br-5MPEPy ( 78 ), and MTEP ( 76 ) all dose-dependently both decreased cocaine self-administration and attenuated the discriminative stimulus effects of cocaine. Moreover, the partial NAMs M-5MPEP ( 77 ) and Br-5MPEPy ( 78 ) demonstrated antidepressant-like and anxiolytic-like activity, corresponding with increasing in vivo mGlu 5 occupancy.…”

Allosteric Modulation of GPCRs: New Insights and Potential Utility for Treatment of Schizophrenia and Other CNS Disorders

“…In addition to differences in terms of stimulus bias, activity at heterodimers, and presence or absence of ago-PAM activity, it has been possible to develop NAMs that possess weak negative cooperativity can act as partial NAMs that only partially inhibit the response to an orthosteric agonist (Kenakin, 2004; Nickols et al, 2016; Rodriguez et al, 2010; Rodriguez et al, 2005). These partial NAMs could provide a key mechanistic advantage that cannot be achieved using orthosteric antagonists and have the potential to maintain efficacy similar to full NAMs in animal models, but have fewer adverse effects than agents that completely block GPCR signaling (Gould et al, 2016). …”

“…However, these findings also raise the question of what signaling pathways and physiological responses are critical for specific in vivo actions of mGlu 5 PAMs. As new tools are further developed that selectively modulate specific signaling pathways by mGlu 5 , they will provide opportunities to develop a full understanding of the specific signaling pathways that are critical for mediating the efficacy of mGlu 5 PAMs in preclinical models of numerous CNS disorders including schizophrenia, fragile X syndrome, Rett syndrome, autistic spectrum disorders, obsessive compulsive disorder, Parkinson's disease, substance abuse (Ade et al, 2016; Gass et al, 2016; Gogliotti et al, 2016; Gould et al, 2016; Michalon et al, 2012; Rylander et al, 2010; Vicidomini et al, 2016), and others.…”

Positional isomers of bispyridine benzene derivatives induce efficacy changes on mGlu5 negative allosteric modulation

“…The discovery of a molecular switch from full allosteric inverse agonists to partial allosteric antagonists is of high interest, since recent publications have reported the advantageous properties of partial mGlu 5 NAMs [40,41], which might avoid on-target side-effects of full mGlu 5 inhibition by classical allosteric inverse agonists [42,43]. Therefore, our approach based on changing substituent positions of molecularly rigid mGlu 5 NAMs may be useful for discovering new partial mGlu 5 NAMs with safer pharmacological profiles and better drug design outcomes.…”