Stereospecificity, drug-receptor

Admittedly, the separation of enantiomers is often difficult and expensive. However, now that we are in the 21st century, the need for optically active drugs capable of stereospecific interactions with drug receptors is a recognized prerequisite in drug design. 

Since the ir value is constitutive, the stereospecific nature of hydro-phobic bonding for drug-receptor interactions can be delineated by regression analyses with the tt values of substituents separately for each position of the congeners. Thus, the substituent effect on the emulsin hydrolysis of substituted phenylglucosides has been nicely delineated by analyzing kinetic constants separately for meta and para isomers. The meta substituents play no hydrophobic role in the enzyme-substrate complex formation 24). 

It seems likely that continuation of the study of partition coefficients will provide a great deal of Information about some of the factors involved in hydrophobic interactions. It does not seem likely that this approach will provide a great deal of information about the detailed mechanisms of stereospecific drugs interacting with stereospecific receptors. 

FIGURE 58-7 The IC50 values (ordinate) are the concentrations of the antipsychotic drugs that reduce the stereospecific component of 3H-haloperidol binding by 50%. The abscissa indicates the average values (and ranges) of doses used for schizophrenia. (From Seeman, P. et al. Antipsychotic drug doses and neuroleptic/dopamine receptors. Nature 261 717-719,1976)... 

Lovell, R. A., and Freedman, D. X. (1976) Stereospecific receptor sites for d-lysergic acid diethylamide in rat brain Effects of neurotransmitters, amine antagonists and other psychotropic drugs. Mol. Pharmacol., 12 620-630. 

Optical isomerism is the result of a dissymmetry in molecular suhstitution. The basic aspects of optical isomerism are discussed in various textbooks of organic chemistry. Optical isomers (enantiomers) may have different physiological activities from each other provided that their interaction with a receptor or some other effector structure involves the asymmetric carbon atom of the enantiomeric molecule and that the three different substituents on this carbon atom interact with the receptor. The Easson-Stedman hypothesis assumes that a three-point interaction ensures stereospecificity, since only one of the enantiomers will fit the other one is capable of a two-point attachment only, as shown in figure 1.13 for the reaction with a hypothetical planar receptor. However, it is reasonable to assume that receptor stereospecificity can also undergo a change when the receptor conformation is altered by a receptor-drug interaction. 

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. 

The bioactivity of a drug is the result of interaction with a biological receptor, a protein molecule with a binding site that is also chiral and stereospecific. The interaction of the D isomer of a drug with a chiral receptor site will differ from the interaction of the L isomer with that site. 

Answer Only one of the two enantiomers of the drug molecule (which has a chiral center) is physiologically active, for reasons described in the answer to Problem 3 (interaction with a stereospecific receptor site). Dexedrine, as manufactured, consists of the single enantiomer (D-amphetamine) recognized by the receptor site. Benzedrine was a racemic mixture (equal amounts of D and l isomers), so a much larger dose was required to obtain the same effect. 

Acquas E, Di Chiara G (1994) Dl-receptor blockade stereospecifically impairs the acquisition of drug-conditioned place preference and place aversion. Behav Pharmacol 5 555-569. 

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