SELECTIVE ALLOSTERIC ENHANCEMENT OF THE BINDING AND ACTIONS OF ACETYLCHOLINE AT MUSCARINIC RECEPTOR SUBTYPES

The ternary allosteric model predicts the possibility of discovering m olecules with novel and highly subtype-selective modes of action. This approach has been applied to muscarinic receptors. The alkaloid bruci ne is capable of selectively enhancing by an allosteric mechanism the effects of low but not high concentrations of acetylcholine at only th e m1 subtype of muscarinic receptors. A simple derivative of brucine, N-chloromethylbrucine, enhances acetylcholine actions selectively at o nly m3 receptors. In addition it binds to, but does not affect, the pr operties of m4 receptors, thereby demonstrating neutral cooperativity and an 'absolute' selectivity of action at m3 receptors over m4 recept ors. Brucine N-oxide enhances acetylcholine binding at m3 and m4 recep tors and is neutral at m1 and m5 receptors. These findings allow the p ossibility of developing muscarinic agents that have a novel and highl y targeted mode of action; they may act only on a single muscarinic re ceptor subtype which is functioning sub-optimally and therefore be of use therapeutically in the early stages of Alzheimer's Disease.