The identification of novel structural compound classes exhibiting high affinity for neuronal nicotinic acetylcholine receptors and analgesic efficacy in preclinical models of pain

Neuronal nicotinic acetylcholine receptors represent a new and potentially useful target for the development of novel non-opioid, non-NSAID (nonsteroi dal antiinflammatory drug) analgesic agents. A variety of nicotinic acetylc holine receptor agonists such as nicotine, epibatidine and the azetidinyl e ther, ( R)-5-(2-azetidinylmethoxy-2 -chloropyridine (ABT-594) pos ses ses s ignificant efficacy in preclinical models of pain. A preponderance of evide nce suggests that nicotinic acetylcholine receptor agonists produce their a nalgesic effects predominantly via activation of descending inhibitory pain pathways originating in the key brainstem regions of the nucleus raphe mag nus, dorsal raphe, and locus coeruleus, and that alpha 4-containing nicotin ic acetylcholine receptor subunits mediate these effects. Although these st udies may provide a pharmacological target for the development of nicotinic acetylcholine receptor analgesics, the rational design of selective ligand s based on the protein structure of the binding site is hampered by insuffi cient structural information. Using an approach based upon homology to know n high-affinity ligands for the alpha 4 beta 2 binding site, a four-point m odel is proposed which defines distance and directionality parameters commo n to this set of nicotinic acetylcholine receptor ligands. (C) 2000 Elsevie r Science B.V. All rights reserved.