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

The α7 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 α7 receptors expressed in Xenopus oocytes, with no significant activation of either α3β4 or α4β2 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 α3β4 and α4β2 receptors, as well as for α7 nAChR. Structural comparison of ACME with the benzylidene anabaseines, another class of previously identified α7-selective agonists, suggests that they share a similar structural motif that may be applicable to other α7-selective agonists.