Zhang_2016_Eur.J.Med.Chem_124_689

We previously reported the cyclopropylpyridine and isoxazolylpyridine ether scaffolds to be versatile building blocks for creating potent alpha4beta2 nicotinic acetylcholine receptor (nAChR) partial agonists with excellent selectivity over the alpha3beta4 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 alpha4beta2* nAChR partial agonists with Ki values of 0.5-51.4 nM for alpha4beta2 and negligible affinities for alpha3beta4 and alpha7. 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(R) platform and classical forced swim tests, supporting the potential use of alpha4beta2 partial agonists for treatment of depression.