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

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:15

Article

Papke, RL ; Zheng, GR ; Horenstein, NA ; Dwoskin, LP ; Crooks, PA

关键词: oocyte;    voltage clamp;    Alzheimer's disease;    schizophrenia;   

DOI  :  10.1016/j.bmcl.2005.05.118

来源: Elsevier

【 摘 要 】

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.

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