We therefore incorporated the 4-chlorobiphenyl-3-carboxylic acid moiety from2into the design of the new analogues. == Table 1. abuse can lead to severe neurotoxicity, psychosis, lethargy, depressive disorder, or potentially death through a fatal overdose. Currently there is no effective treatment for cocaine dependence, and therefore cocaine dependency constitutes a major public health problem. Consequently, there is a Pax1 significant need to identify new therapeutic agents for the treatment of cocaine and other psychomotor stimulant addictions. Recent findings suggest that neuroadaptations in glutamatergic transmission produced by repeated exposure to cocaine or other drugs of abuse are likely to contribute CL-387785 (EKI-785) to the maintenance of addictive behaviors including drug use, craving and relapse to drug taking in humans.3Specifically, it has been shown that repeated cocaine exposure alters the function of Group II metabotropic glutamate receptors (mGluRs).4aThe Group II mGluRs include the mGluR2 and mGluR3 subtypes, which couple to Gi/oproteins to negatively regulate the activity of adenylyl cyclase. 4bBrain 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,5suggesting a role for the mGluR2/3 subtypes in the development of cocaine dependence and as potential targets for therapeutic brokers.3a,3e,3f,6 Orthosteric (glutamate site) mGluR2/3 agonists such asLY3792686gare 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 receptors.6hLY379268has been shown to decrease glutamate levels7and to attenuate cocaine self-administration both in rats6c,8and in squirrel monkeys.6aHowever,LY379268also inhibits responding for food and food-seeking behavior6c,6e,9, suggesting that mGluR2/3 CL-387785 (EKI-785) agonists exhibit non-selective actions on responding for drug and non-drug reinforcers. We recently initiated investigations to determine the effect of selectively activating mGluR2 on cocaine dependence.8Localization studies CL-387785 (EKI-785) suggest that mGluR2 acts predominantly as a presynaptic autoreceptor to modulate the release of glutamate into the synaptic cleft.10In recent years, there have been several reports on the use of high-throughput screening (HTS) for the identification of small molecule mGluR2 positive allosteric modulators (PAMs).11The activity of these compounds is of interest because of their subtype-selectivity, ability to overcome receptor desensitization and potential for improved drug-like properties.12The use of a selective mGluR2 PAM in an appropriatein vivomodel therefore represents a stylish approach to elucidate the role of mGluR2 in cocaine dependence. We previously disclosed the structure activity relationship (SAR) around a series of pyrimidine derivatives with activity as mGluR2 PAMs.11bThe synthesis and characterization of 3-((2-cyclopentyl-6,7-dimethyl-1-oxo-2,3-dihydro-1H-inden-5-yloxy)methyl)biphenyl-4-carboxylic acid (BINA,1) has been previously reported13and we have shown that this compound possesses antipsychotic and anxiolytic effects in mice.14Most relevant to the present report, we recently showed that compound1,unlike mGluR2/3 agonists, decreased cocaine self-administration in rats at doses that did not affect responding for food.8A recent report by the Merck group on a series of oxazolobenzimidazole-based mGluR2 PAMs that are orally active in anin vivomodel of schizophrenia prompts us to disclose our own efforts around the development of orally active mGluR2 PAMs.15b While compound1is brain penetrant and selective, it lacks potency for mGluR2 bothin vitroandin vivoand has sub-optimal pharmacokinetic (PK) properties. We therefore set out to design and synthesize new selective mGluR2 PAMs based on the compound1scaffold in order to improve both potency and PK properties. These new PAMs are suitable forin vivoproof-of-concept (POC) studies to evaluate the potential of mGluR2 as a therapeutic target for the treatment of cocaine dependence. We hypothesized that modifying the indanone ring of1by incorporating heteroatoms may lead to analogues with improved properties (Physique 1). Interestingly, to date there have been no reports around the synthesis and evaluation of analogues of compound1in which the indanone ring has been systematically modified in this way. In addition, as far as we are aware there have been no studies documenting the effects of modifying the cyclopentyl ring in this scaffold. Furthermore, despite several recent reports disclosing mGluR2 PAMs,11,15none have been evaluated in anin vivomodel of medication dependence. == Shape 1. == Incorporation of heteroatoms into BINA (1). Primarily, we.