Recent findings suggest that neuroadaptations in glutamatergic transmission produced by repeated exposure to drugs of abuse such as cocaine or nicotine are likely to contribute to the maintenance of addictive behaviors including drug use, craving and relapse to drug taking in humans. Specifically, it has been shown that repeated cocaine exposure alters the function of the Group II metabotropic glutamate mGlu2 and mGlu3 receptors. Furthermore, nicotine increases glutamatergic neurotransmission by activating excitatory nicotinic acetylcholine (nACh) receptors located on presynaptic glutamatergic terminals. The Group II mGlu receptors, which couple to Gi/o proteins to negatively regulate the activity of adenylyl cyclase, are primarily localized presynaptically and modulate glutamate release. 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 mGlu2 and mGlu3 receptor binding, suggesting a role for the mGlu2/3 receptor subtypes in the development of nicotine dependence and as potential targets for therapeutic agents. We previously reported our preliminary results on a novel series of mGlu2 receptor positive allosteric modulators (PAMs). Using the mGlu2 receptor PAM 3'-((2-cyclopentyl-6,7-dimethyl-1-oxo-2,3-dihydro-1H-inden-5-yloxy)methyl)biphenyl-4-carboxylic acid (biphenyl indanone-A, BINA) as a starting scaffold we designed and synthesized new mGlu2 receptor PAMs that are significantly more potent than BINA in vitro and possess superior drug-like properties. We also recently reported the design, synthesis and characterization of mGlu2/3 receptor PAMs with in vivo activity. From these two series we have identified compounds which are active in behavioral models of self-administration in rats, providing proof-of-concept for the use of Group II mGlu receptor PAMs for the treatment of substance abuse.

Design, synthesis, and preclinical characterization of small molecule group II metabotropic glutamate receptor positive allosteric modulators

2019 Fall National Meeting

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