The characterization of a novel rigid nicotine analog with alpha7-selective nAChR agonist activity and modulation of agonist properties by boron inclusion

Bioorg Med Chem Lett. 2005 Sep 1;15(17):3874-80. doi: 10.1016/j.bmcl.2005.05.118.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Boron / chemistry
  • Boron / pharmacology*
  • Brain / metabolism
  • Electrophysiology
  • Humans
  • Nicotine / analogs & derivatives*
  • Nicotine / metabolism
  • Nicotinic Agonists / chemistry*
  • Nicotinic Agonists / pharmacology
  • Oocytes
  • Protein Binding
  • Radioligand Assay
  • Rats
  • Receptors, Nicotinic / drug effects*
  • Structure-Activity Relationship
  • Transfection
  • Xenopus
  • alpha7 Nicotinic Acetylcholine Receptor

Substances

  • Chrna7 protein, human
  • Chrna7 protein, rat
  • Nicotinic Agonists
  • Receptors, Nicotinic
  • alpha7 Nicotinic Acetylcholine Receptor
  • nicotinic receptor alpha3beta4
  • nicotinic receptor alpha4beta2
  • Nicotine
  • Boron