Drug stereospecificity

Mehvar, R. Jamah, F. Bioequivalence of chiral drugs, stereospecific versus non-stereospecific methods. Clin. Phar-macokin. 1997, 33 (2), 122-141. 

J. Caldwell, Importance of stereospecific bioanalytical monitoring in drug development, J. Chro-matogr. A 1996, 719, 3-13. 

We have developed the efficient synthesis of the SERM drug candidate 1 and successfully demonstrated the process on a multiple kilogram scale to support the drug development program. A novel sulfoxide-directed borane reduction of vinyl sulfoxides was discovered. The mechanistic details of this novel reaction were explored and a plausible mechanism proposed. The sequence of asymmetric oxidation of vinyl sulfoxides followed by stereospecific borane reduction to make chiral dihydro-1,4-benzoxathiins was applied to the asymmetric synthesis of a number of other dihydro-1,4-benzoxathiins including the sweetening agent 67. 

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. 

Ariens, E. J. Stereospecificity of bioactive agents General aspects of exemplified by pesticides and drugs. In Stereoselectivity of Pesticides, Biological and Chemical Problems Chemicals in Agriculture, Vol. 1, Ariens, E. J., van Rensoen, J. J. S. W. W., Eds., Elsevier Science, New York, 1988. 

The RIA-procedure for propranolol is solely based on antisera derived from conjugates through the asymmetric carbon (i.e., the optical carbon) as shown in the above chemical structures. Perhaps it could be possible that the stereospecificity of propranolol is caused due to the conformation of the drug-hapten in relation to the carrier protein to a great extent, through this hypothesis remains to be ascertained scientifically. 

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. 

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. 

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. 

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