Title | Drug stereochemistry and stereoselectivity implications in clinical pharmacology | |
Authors | Charalambos T. Plessas¹, Stavros T. Plessas¹ and Achilles Benakis²
1. PHARMAKON-Press Information Services, Athens, Greece 2. Laboratory of Drug Metabolism, Department of Pharmacology, University of Geneva, Switzerland. |
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Citation | Plessas, C.T., Plessas, S.T., Benakis, A.: Drug stereochemistry and stereoselectivity implications in clinical pharmacology, Epitheorese Klin. Farmakol. Farmakokinet. 2(2): 67-84 (1988) | |
Publication Date | 1988-10 | |
Full Text Language | English | |
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Keywords | Stereochemistry, stereoselectivity, drugs, implications, clinical pharmacology, biomolecules, proteins, carbohydrates, neurotransmitters, hormones, bioactive agents. | |
Other Terms | review article | |
Summary | All living organisms are constituted of ordered asymmetric biomolecules, such as proteins (receptors, enzymes, antibodies), carbohydrates, neurotransmitters, hormones etc., due to the special geometry of one or more of their carbon atoms. The asymmetry is not restricted to the biogenic compounds; a great number of xenobiotics (drugs, pesticides, food additives, environmental pollutants) thought to be monosubstances are in fact mixtures consisting of two enantiomers (racemates). Enantiomers are chemically very similar molecules, since they are a mirror image of one another, but their physical, chemical, stereochemical and biological properties are generally very different Bioactive substances selectively interact with specific sites of enzymes, receptors, carriers molecules etc. This binding, accounting for biological actions, biotransformation, or carrier mechanisms, requires stereochemical complementarity between bioactive molecule and target site. The complementarity between the interactants can be regarded as stamp-print or positive-negative relation, but a truer picture is obtained with three-dimentional models on which the three-point interaction concept is based. The enantiomers quite often exhibit pronounced differences in their pharmacological and toxicological properties both in qualitative and quantitative terms. In addition, drugs and other bioactive agents are usually given as racemates. As a rule the therapeutic activity of the racemate may be due mainly to one of the enantiomers, the eutomer, while the other one, the distomer, may be responsible for the side effects, have different therapeutic activities (sometimes even antagonistic) or be pharmacologically inert. The stereoselective metabolic inversion of one isomer to the other is also very interesting; this is particularly the case of 2-aryfpropionic acid derivatives. The nature and the extent of these differences are illustrated by examples of some well-known and widely used drugs, such as β– adrenergic blocking agents (propranolol, timolol, satoiol, labetalol, medroxalol), quinidine and quinine, barbiturates, dobutamine, non-steroidal anti-inflammatory agents derivatives of 2 aryl- propionic acid (ibuprofen, benoxaprofen, cicloprofen, clidanac, naproxen), indacrinone, ketamine, levamisole, levodopa, pentazocine, propoxyphene, prilocaine, tranylcypromine and verapamil. | |
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