A new look at the neuronal nicotinic acetylcholine receptor pharmacophore

Interest in the field of nicotinic receptors has been recently stimulated b oth 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 exoge nous system allows their study in isolation. Receptors reconstituted by pai rwise injection of either alpha 4 or alpha 3 with beta 2 or beta 4 subunits displayed important differences between the resulting receptor subtypes. T hese results were further compared with those obtained with alpha 3:alpha 4 fusion proteins. The modifications of either the ligand-binding site in th e N-terminal domain or in the ionic pore domain were found to affect the ph armacological properties of the receptors. Finally, the analysis of non-nat ural 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.