The characterization of a novel rigid nicotine analog with alpha7-selective nAChR agonist activity and modulation of agonist properties by boron inclusion.
The alpha7 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 alpha7 receptors expressed in Xenopus oocytes, with no significant activation of either alpha3beta4 or alpha4beta2 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 alpha3beta4 and alpha4beta2 receptors, as well as for alpha7 nAChR. Structural comparison of ACME with the benzylidene anabaseines, another class of previously identified alpha7-selective agonists, suggests that they share a similar structural motif that may be applicable to other alpha7-selective agonists.
Papke
Roger L
RL
University of Florida, College of Medicine, 1600 SW Archer Road, Gainesville, FL 32610, USA. rlpapke@ufl.edu
Zheng
Guangrong
G
Horenstein
Nicole A
NA
Dwoskin
Linda P
LP
Crooks
Peter A
PA
D000818:Animals; D001895:Boron / Q000737:chemistry / Q000494:pharmacology*; D001921:Brain / Q000378:metabolism; D004594:Electrophysiology; D006801:Humans; D009538:Nicotine / Q000031:analogs & derivatives* / Q000378:metabolism; D018722:Nicotinic Agonists / Q000737:chemistry* / Q000494:pharmacology; D009865:Oocytes; D011485:Protein Binding; D011869:Radioligand Assay; D051381:Rats; D011978:Receptors, Nicotinic / Q000187:drug effects*; D013329:Structure-Activity Relationship; D014162:Transfection; D014981:Xenopus; D064569:alpha7 Nicotinic Acetylcholine Receptor
C579167:Chrna7 protein, human; C579165:Chrna7 protein, rat; D018722:Nicotinic Agonists; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; C403530:nicotinic receptor alpha3beta4; C403531:nicotinic receptor alpha4beta2; D009538:Nicotine; D001895:Boron