Synthesis and biological evaluation of novel hybrids of highly potent and selective a4ß2-Nicotinic acetylcholine receptor (nAChR) partial agonists

Abstract

© 2016 Elsevier Masson SASWe previously reported the cyclopropylpyridine and isoxazolylpyridine ether scaffolds to be versatile building blocks for creating potent a4ß2 nicotinic acetylcholine receptor (nAChR) partial agonists with excellent selectivity over the a3ß4 subtype. In our continued efforts to develop therapeutic nicotinic ligands, seven novel hybrid compounds were rationally designed, synthesized, and evaluated in [3H]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 a4ß2* nAChR partial agonists with Ki values of 0.5–51.4 nM for a4ß2 and negligible affinities for a3ß4 and a7. Moreover, compounds 21, 25, and 30 maintained the functional profiles (EC50 and IC50 values of 15–50 nM) of the parent azetidine-containing compounds 3 and 4 in the 86Rb+ ion flux assays. In vivo efficacy of the most promising compound 21 was confirmed in the mouse SmartCube® platform and classical forced swim tests, supporting the potential use of a4ß2 partial agonists for treatment of depression.