Synthesis and biological evaluation of novel hybrids of highly potent and selective α4β2-Nicotinic acetylcholine receptor (nAChR) partial agonists

We previously reported the cyclopropylpyridine and isoxazolylpyridine ether scaffolds to be versatile building blocks for creating potent α4β2 nicotinic acetylcholine receptor (nAChR) partial agonists with excellent selectivity over the α3β4 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 42* nAChR partial agonists with Ki values of 0.5–51.4 nM for 42 and negligible affinities for 34 and 7. 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 42 partial agonists for treatment of depression.