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L. YU, H.K. ZHANG1, J. EATON, M. NYS, A. MAZZOLARI, R. VAN ELK, A. B. SMIT, T. HANANIA, D. BRUNNER, R. J. LUKAS, G. VISTOLI, C. ULENS, A. P. KOZIKOWSKI

Neuronal nicotinic acetylcholine receptors (nAChRs) belong to the ligand-gated ion channel super-family of neurotransmitter receptors, which are widely distributed in both the central and peripheral nervous systems. It is well known from the literature that the specific blockade (antagonism or receptor desensitization) of α4β2-nAChRs results in antidepressant-like effects, and thus that appropriate nAChR ligands may offer therapeutic benefits to patients who do not respond to SSRIs. In this study, an integrated approach has been used to develop novel, behaviorally active α4β2-nAChR ligands for possible use in clinical depression. An X-ray co-crystal structure of AChBP from Capitella teleta in complex with our recently developed cyclopropane-containing, α4β2-nAChRselective partial agonist was acquired at a resolution of 2.3 Å. These data reveal that our cyclopropane containing ligand shares a common mode of interaction with the protein as found for varenicline, the currently marketed α4β2 -nAChRs ligand that has been approved for smoking cessation. The X-ray data has in turn been used to further refine our previous model of the human α4β2 receptor. Homology modeling methods combined with in silico ADME calculations have aided the rational design of other cyclopropane-containing ligands that act as α4β2- nAChR-selective partial agonists. One of the most active compounds exhibited an improved metabolic stability in comparison to the parent compound, while retaining favorable pharmacological parameters, together with appropriate behavioral endpoints in the rodent studies. Taken together, the X-ray co-crystal structure of our ligand in complex with the Ct-AChBP allows us to better advance our structure-based drug design efforts, which may find use in treatment resistant forms of depression.