[Contribution of stereochemistry to the study of the spatial organization of pharmacological receptors]

Abstract

The important discovery by Pasteur of optical isomerism and the recent developments of stereochemistry showed that a complementarity exist between the geometry of molecules and their pharmacological receptors. The stereochemical bases and the principal configurational nomenclatures are briefly overviewed. The stereospecificity of the biological response and theories leading to an approach to stereochemical structures of main pharmacological receptors are developed. So, the biological activity of steroids is due to junctional modes of cycles and alpha or beta configurations of substituents. Acetylcholine has a skew conformation but it react by an anticlinal/anti-planar conformation with muscarinic receptor. To explain the difference in activity of adrenaline enantiomers, Easson and Stedman proposed a "three points" fixation to the adrenergic receptor. Dopaminergic receptor present a good degree of stereoselectivity: dopamine act by an anti-planar conformation in which the N-O distance is the same as in apomorphine (N-O10). The analgesic activity of morphinans is due to a cis junction of B and C cycles and to the stereoelectronic effect of the unshared lone pair on nitrogen. In the cyclamate sweeteners, some authors proposed for the sweet taste receptor a model with two points fixation (one acceptor and one donor) and two spatial barriers located at precise distances from this two sites. The stereoselectivity of molecules acting as substrates or inhibitors of enzymes is described. For example some oxazolidinone derivatives showed a selective inhibition toward monoamine oxidase A. Finally, the pharmacological activity falls often when molecules are administrated in racemic form. It seems that xenobiotics need to be dissymmetric for chiral recognition by biological systems.