The characterization of a novel rigid nicotine analog with α7-selective nAChR agonist activity and modulation of agonist properties by boron inclusion

The alpha 7 nAChR subtype is of particular interest as a potential therapeutic target since it has been implicated as a mediator of both cognitive and neuroprotective activity. The rigid nicotine analog ACME and the N-cyanoborane conjugate ACME-B are selective partial agonists of rat alpha 7 receptors expressed in Xenopus oocytes, with no significant activation of either alpha 3 beta 4 or alpha 4 beta 2 receptors. ACME-B is both more potent and efficacious than ACME. The efficacies of ACME-B and ACME are approximately 26% and 10% of the efficacy of ACh, respectively. Similar N-conjugation of S(-)nicotine with cyanoborane decreased efficacy for alpha 3 beta 4 and alpha 4 beta 2 receptors, as well as for alpha 7 nAChR. Structural comparison of ACME with the benzylidene anabaseines, another class of previously identified alpha 7-selective agonists, suggests that they share a similar structural motif that may be applicable to other alpha 7-selective agonists. (c) 2005 Elsevier Ltd. All rights reserved.