Synthesis And Biological Evaluation Of Novel Hybrids Of Highly Potent And Selective Î±4Î²2-Nicotinic Acetylcholine Receptor (Nachr) Partial Agonists
We previously reported the cyclopropylpyridine and isoxazolylpyridine ether scaffolds to be versatile building blocks for creating potent Î±4Î²2 nicotinic acetylcholine receptor (nAChR) partial agonists with excellent selectivity over the Î±3Î²4 subtype. In our continued efforts to develop therapeutic nicotinic ligands, seven novel hybrid compounds were rationally designed, synthesized, and evaluated in [ 3 H]epibatidine binding competition studies. Incorporation of a cyclopropane- or isoxazole-containing side chain onto the 5-position of 1-(pyridin-3-yl)-1,4-diazepane or 2-(pyridin-3-yl)-2,5-diazabicyclo[2.2.1]heptane led to highly potent and selective Î±4Î²2* nAChR partial agonists with K i values of 0.5â€“51.4Â nM for Î±4Î²2 and negligible affinities for Î±3Î²4 and Î±7. Moreover, compounds 21, 25, and 30 maintained the functional profiles (EC 50 and IC 50 values of 15â€“50Â nM) of the parent azetidine-containing compounds 3 and 4 in the 86 Rb + ion flux assays. InÂ vivo efficacy of the most promising compound 21 was confirmed in the mouse SmartCube Â® platform and classical forced swim tests, supporting the potential use of Î±4Î²2 partial agonists for treatment of depression.
European Journal of Medicinal Chemistry
Digital Object Identifier (DOI)
Zhang, Han Kun; Eaton, J. Brek; Fedolak, Allison; Gunosewoyo, Hendra; Onajole, Oluseye K.; Brunner, Dani; Lukas, Ronald J.; Yu, Li Fang; and Kozikowski, Alan P., "Synthesis And Biological Evaluation Of Novel Hybrids Of Highly Potent And Selective Î±4Î²2-Nicotinic Acetylcholine Receptor (Nachr) Partial Agonists" (2016). Translational Neuroscience. 279.