Stereoisomers receptor binding

Levin AA, Sturzenbecker LJ, Kazmer S, et al (1992) 9-cis Retinoic acid stereoisomer binds and activates the nuclear receptor RXR alpha. Nature 355 359-361... 

The P receptor is highly stereospecific, preferentially binding only to certain stereoisomers of drugs. The conformational preference is a phenyl/NHj trans arrangement, meaning that the agonist molecule is extended, with the m-OH and 8-OH coincident on the same face of the molecule. The agonist molecule therefore has a polar and a nonpolar side. 

Cartoon illustrating the nonsuperimposibility of the two stereoisomers of carvedilol on the 13 receptor. The "receptor surface" has been grossly oversimplified. The chiral center carbon is denoted with an asterisk. One of the two isomers fits the three-dimensional configuration of binding site of the 13-... 

The extent and degree of interactions between chiral macromolecules of the body and stereoisomers is a source of observable differences in isomeric drug distribution. Stereoselectivity in drug distribution may occur when tissue or protein binding or uptake is associated with structurally specific receptor, protein, or enzyme binding. Since only unbound or free drug is susceptible to elimination and distribution to receptors and other tissues and fluids, differences in the protein and tissue binding of stereoisomers are reflected in their overall pharmacokinetic profiles. 

In addition to the fact that most receptors are asymmetric, there are other reasons why. stereoisomers show different biological response.s. Active traasport mechanisms involve asymmetric carrier molecules, which means that there will be preferential binding of one stereoisomer over others. When differences in physical properties exist, the distribution of isomers between body fluids and tissues where the receptors are located will differ. The enzymes responsible for drug metabolism are asymmetric, which means that biological half-lives will differ among possible stereoisomers... 

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