New quinoline derivatives as nicotinic receptor modulators

As a continuation of previous work on quinoline derivatives, which showed some preference (2-3 times) for the alpha 7 with respect to alpha 4 beta 2 acetylcholine nicotinic receptors (nAChRs), we synthesized a series of novel azabicyclic or diazabicyclic compounds carrying a quinoline or isoquinoline ring, with the aim of searching for more selective alpha 7 nAChR compounds. Radioligand binding studies on alpha 7* and alpha 4 beta 2* nAChRs (rat brain homogenate) revealed one compound (7) with a 2-fold higher affinity for the alpha 4 beta 2*-subtype, and four compounds (11, 13, 14 and 16) with at least 3-fold higher affinity for alpha 7* nAChR. The most promising was 11, showing K-i similar to 100 nM and over 10-fold selectivity for alpha 7* nAChR. Compounds 7,11, 13 and 16 at 50 mu M suppressed ion currents induced in the rat alpha 4 beta 2 nAChR and the chimeric nAChR composed of the ligand-binding domain of the chick alpha 7 and transmembrane domain of the alpha 1 glycine receptor, expressed in Xenopus oocytes. Calcium imaging experiments on the human a7 nAChR expressed in the Neuro2a cells and potentiated by PNU-120596 confirmed the antagonistic activity for alpha 7; on the contrary, 11, 13 and 16 were agonists with the EC50 values in the range of 1.0-1.6 mu M. Thus, the introduced modifications allowed us to enhance the selectivity of quinolines towards alpha 7 nAChR and to get novel compounds with agonistic activity. (C) 2016 Elsevier Masson SAS. All rights reserved.