Design, synthesis and evaluation of novel group II metabotropic glutamate receptor allosteric modulators in rodent models of CNS disorders

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The Group II metabotropic glutamate (mGlu) receptors include the mGlu2 and mGlu3 receptor subtypes and couple via Gi/o proteins to negatively regulate the activity of adenylyl cyclase. Localization studies suggest that mGlu2 receptors act as presynaptic autoreceptors to modulate release of glutamate, whereas mGlu3 receptors exhibit a broad distribution in the brain and have been shown to be present on astrocytes [1]. 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. Repeated cocaine exposure alters the function of mGlu2 and mGlu3 receptors while nicotine increases glutamatergic neurotransmission by activating excitatory nicotinic acetylcholine (nACh) receptors located on glutamatergic terminals. Brain regions implicated in different aspects of drug abuse and drug dependence display high levels of mGlu2 and mGlu3 receptor binding, suggesting a role for mGlu2/3 receptors in the development of drug dependence and as potential targets for therapeutic agents. We recently reported data on selective mGlu2 receptor positive allosteric modulators (PAMs) in models of drug dependence [2–4]. We now report the design and synthesis of novel, systemically active PAMS that selectively modulate both mGlu2 and mGlu3 receptors. Structure-activity relationship (SAR) data on this series will be described in addition to results from behavioral models of self-administration in rats.

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