Stereospecificity of drug

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. 

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. 

Racemization is the process of changing from an optically active compound into a racemic mixture. Pfeiffer provided one of the earliest discussions on the importance of stereospecificity in drug action [22]. 

Thus the (R) form cannot correctly be described as inert. Statements such as the (R) form is inert and the (S) form is pharmacologically active and is therefore also responsible for adverse side effects must be examined carefully and tested by experiments which are capable of measuring stereospecific differences. In the monitoring of drug levels and metabolites in body fluids, methods which do not distinguish between the (R) and (S) forms of chiral drugs and their metabolites are likely to yield pharmacokinetic nonsense. 

Testa B, Jenner P (1976) Drug metabolism chemical and biochemical aspects. Part II Biochemical aspects of drug oxidation. In Swarbrick J (ed) Drug and the pharmaceutical science. Marcel Dekker, New York, pp 271-312 Wittman MD, Kadow JK, Vyas DM (2000) Stereospecific synthesis of the major human metabolite of paclitaxel. Tetrahedron Lett 41 4729... 

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. 

In the past, pharmacokinetic and pharmacodynamic investigations of chiral drugs have neglected the influences of stereoisomerism. This is primarily a result of the lack of stereospecific analysis procedures. Nonstereospecific assays give pharmacokinetic and pharmacodynamic information which represents a complex combination of the characteristics of the separate stereoisomers. With the advent of stereospecific analysis procedures a better understanding of drug kinetics and action as possible. 

Milne, G.M. Koe, B.K. and Johnson, M.R. Stereospecific and potent analgetic activity for nantradol - A structurally novel, cannabinoid related analgetic. In Harris, L.S., ed. Problems of Drug Dependence, 1979. National Institute on Drug Abuse Research Monograph 27. DHEW Pub. No. (ADM) 80-901. Wash., D.C. Supt. of Docs., U.S. Gov. Print. Off., 1980. 84-92. 

A number of recent studies extend the observation of stereoselectivity of drug metabolism. The inactive d-isomer of propanolol was metabolized in rats with a two-fold shorter plasma half-life than l-propanolol . The anti-inflammatory agent l-a-methylfluorene-2-acetic acid was isomerized in dogs to the d-enantiomer , thus being another example of stereospecific metabolic inversion. Whereas the individual R and S enantiomers of 15 were metabolized at similar rates, the half-life of the more active R isomer was prolonged in the racemic mixture, perhaps due to inhibition of metabolism of the R isomer by the S isomer. A similar effect was observed with the R and S enantiomers of amphetamines , which further illustrates that racemates may exhibit a biological profile different from that anticipated on the basis of the activity of the component enantiomers. 

Because many drugs contain either chiral centers, prechiral centers, or both, interest in stereochemical substrate-enzyme interactions, the stereospecificity of biotransformations, and species (and strain) differences in these parameters is increasing. Since enzymes themselves contain chiral centers, differential interaction of R and S isomers of drugs with drug metabolizing enzymes is the rule rather than the exception. Beckett reported stereoselectivity in the N-dealkylation, deamination, and formation of the nitrone and secondary hydroxylamine metabolites (+) -and (-) - N-benzylamphetamine ( ) in rabbits. Stereoselectivity has also been observed in the dealkylation of d-, 1-, and d,1-fenfluramine (22), an anorexiogenic agent. 

Frequently one of the enantiomers does not have active pharmacologic properties. In such a case, the drug formulation should not include a chemical moiety that does not have therapeutic value once the separation technique is available and is considered to be economical. In addition to physiological activities, stereospecificity influences the physicochemical properties of drugs. Let s take as an example the enantiomer of ibuprofen compared with the race-mate. The chiral compound has higher aqueous solubility, higher density, and better flowability, but a lower intrinsic dissolution rate. ... 

Table 5-6. Relative Potencies of Drugs in Reducing Stereospecific 3H-Naloxone Binding to Rat Brain Homogenate...

EDj0 = concentration of drug required to inhibit stereospecific 3H-naloxone binding by 50%. (From Pert and Snyder, 1973b.)... 

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