Design and Synthesis of an Orally Active Metabotropic Glutamate Receptor Subtype-2 (mGluR2) Positive Allosteric Modulator (PAM) That Decreases Cocaine Self-Administration in Rats

Abstract

The modification of 3′-((2-cyclopentyl-6,7-dimethyl-1-oxo-2,3-dihydro-1H-inden-5-yloxy)methyl)biphenyl-4-carboxylic acid (BINA, 1) by incorporating heteroatoms into the structure and replacing the cyclopentyl moiety led to the development of new mGluR2 positive allosteric modulators (PAMs) with optimized potency and superior drug-like properties. These analogues are more potent than 1 in vitro, and are highly selective for mGluR2 vs. other mGluR subtypes. They have significantly improved pharmacokinetic (PK) properties, with excellent oral bioavailability and brain penetration. The benzisothiazol-3-one derivative 14 decreased cocaine self-administration in rats, providing proof-of-concept for the use of mGluR2 PAMs for the treatment of cocaine dependence. KeywordsMetabotropic glutamate receptors; agonist; positive allosteric modulators; BINA; cocaine selfadministration Cocaine addiction is a chronic relapsing disorder affecting more than 1.6 million Americans. 1 Relapse rates among cocaine users is in the range of 94-99%, the highest among all commonly abused drugs. 2 Chronic cocaine abuse can lead to severe neurotoxicity, psychosis, lethargy, depression, or potentially death through a fatal overdose. Currently there is no effective treatment for cocaine dependence, and therefore cocaine addiction constitutes a major public health problem. Consequently, there is a significant need to identify new therapeutic agents for the treatment of cocaine and other psychomotor stimulant addictions. Recent findings suggest that neuroadaptations in glutamatergic * Corresponding Author: To whom correspondence should be addressed. ncosford@sanfordburnham.org. † These authors contributed equally to this work. NIH Public AccessAuthor Manuscript J Med Chem. Author manuscript; available in PMC 2012 January 13. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript transmission produced by repeated exposure to cocaine or other drugs of abuse are likely to contribute to the maintenance of addictive behaviors including drug use, craving and relapse to drug taking in humans. 3 Specifically, it has been shown that repeated cocaine exposure alters the function of Group II metabotropic glutamate receptors (mGluRs). 4a The Group II mGluRs include the mGluR2 and mGluR3 subtypes, which couple to G i/o proteins to negatively regulate the activity of adenylyl cyclase. 4b Brain regions implicated in different aspects of drug abuse and drug dependence, including the cerebral cortex, hippocampus, striatum, amygdala, frontal cortex and nucleus accumbens display high levels of mGluR2 and mGluR3 binding, 5 suggesting a role for the mGluR2/3 subtypes in the development of cocaine dependence and as potential targets for therapeutic agents. 3a,3e,3f,6 Orthosteric (glutamate site) mGluR2/3 agonists such as LY379268 6g are constrained amino acid analogues that do not exhibit selectivity for mGluR2 versus mGluR3, presumably because of the high degree of sequence homology at the glutamate binding site for these two recept...

The Novel Metabotropic Glutamate Receptor 2 Positive Allosteric Modulator, AZD8529, Decreases Nicotine Self-Administration and Relapse in Squirrel Monkeys

“…To the degree that these results are mediated by mGluR2 (as suggested by the present findings with AZD8529 and the previous findings with BINA and a related PAM of GluR2; (21, 27), these observations may have implications for relapse prevention across drug classes. This is because of the well-established co-morbidity between nicotine addiction and alcoholism (49, 50), as well as addiction to other drugs like THC, methamphetamine, heroin, and cocaine (51-53).…”

“…LY379268 has low bioavailability (21) and tolerance develops to its effects (20). Additionally, LY379268 activates the mGluR3 subtype whose physiological functions are unknown (8).…”

“…They also reported that a BINA analogue with superior pharmacokinetic properties and brain penetration decreases nicotine self-administration in rats (21). Based on these studies, we used our squirrel monkey model (28, 29) to determine the effects of AZD8529, a selective PAM for mGluR2 (30), on nicotine self-administration and relapse to nicotine seeking, as assessed in the reinstatement procedure (31).…”

Metabotropic Glutamate Receptor 2 Activators

“…18) and benzoisoxazolones (44, Fig. 18) [105][106][107]. This approach delivered highly selective compounds for the mGlu2 receptor with significantly better PK profiles.…”

The [18F]FDG μPET Readout of a Brain Activation Model to Evaluate the Metabotropic Glutamate Receptor 2 Positive Allosteric Modulator JNJ-42153605

“…In addition to mGluR2 and mGluR2/3 agonists, compounds that can increase the effect of glutamate by binding to the aforementioned allosteric sites , called positive allosteric modulators (PAMs), are being investigated (Johnson et al, 2003;Galici et al, 2006;Dhanya et al, 2011;Fell et al, 2011;Lundström et al, 2011;Cid et al, 2012). The use of PAMs compared with agonists has the advantage of a higher selectivity and potentially overcoming the desensitization of G protein-coupled receptors observed after repeated dosing of agonists (Bonnefous et al, 2005).…”