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J. B.EATON, HAN-KUN ZHANG, LI YU, T HANANIA, E SABATH, A FEDOLAK, L LUCERO, D BRUNNER, A. P. KOZIKIWSKI, R. J. LUKAS

Depression is among the most common and debilitating symptoms of psychiatric disorders and has thus been the subject of extensive scientific study. However, despite the successes so far, currently available pharmacotherapeutics have a number of shortcomings including limited efficacy, a need for chronic administration before achieving efficacy, and undesirable side effects ranging from nausea and loss of libido to suicidal ideation and mania. Rather than attempt to make improvements on currently available classes of drugs, we have spent the last few years generating and testing a library of novel compounds acting at α4β2-nAChR as partial agonists and desensitizers with a high degree of selectivity for this subtype. Here we detail the strategy and report the progress to date of a multi-disciplinary, multi-institutional, and cooperative partnership between government, academia, and industry in the effort to produce novel compounds ready for clinical trials. Thus far, the project has met the goal of producing many compounds that are highly selective for the α4β2-nAChR subtype, more specifically – for the high sensitivity isoform, highly potent, and have range of efficacies as agonists. Starting with sazetidine-A (AMOP-H-OH) as the parent compound, the metabolically unfavorable alkynyl group was replaced with cyclopropane or aromatic rings. Likewise, the pyridine core and azetidine moiety have been substituted, and variation of the hydrocarbon side chain with amine and halide substituents has been explored. In behavioral models, many compounds predictably have favorable antidepressant profiles, thus validating the strategy of in vitro pharmacology-based prioritization of ligands and of targeting ligands with selectivity for and high potency at the α4β2-nAChR high sensitivity isoform. This success allows us now to extend our continuing efforts in preclinical drug discovery to clinical development of our lead compounds. Currently, we have reason to be optimistic for a full, bench-to-clinic translation of the project.