A new look at the neuronal nicotinic acetylcholine receptor pharmacophore

Interest in the field of nicotinic receptors has been recently stimulated both by the discovery of the potential therapeutic effects of new agonists, and by the discovery of an association between nicotinic receptor mutations and human neurological diseases. Expression of human receptors in an exogenous system allows their study in isolation. Receptors reconstituted by pairwise injection of either alpha 4 or alpha 3 with beta 2 or beta 4 subunits displayed important differences between the resulting receptor subtypes. These results were further compared with those obtained with alpha 3:alpha 4 fusion proteins. The modifications of either the ligand-binding site in the N-terminal domain or in the ionic pore domain were found to affect the pharmacological properties of the receptors. Finally, the analysis of non-natural derivatives of epibatidine demonstrates how an agonist can be modified to be selective at one receptor subtype or to become an antagonist. These data are well explained on the basis of a three-state allosteric model. (C) 2000 Elsevier Science B.V. All rights reserved.