Synthesis and pharmacological evaluation of conformationally constrained models of hydrocortisone
The study of conformation in drug action can be approached from two directions, (i) that of the drug, and (ii) that of the receptor. Since the problem of elucidating the biologically active conformation of drug molecules has been extensively studied and is very well reviewed1,2, it should be equally...
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| Format: | Others |
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Scholarly Commons
1974
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| Online Access: | https://scholarlycommons.pacific.edu/uop_etds/1852 https://scholarlycommons.pacific.edu/cgi/viewcontent.cgi?article=2851&context=uop_etds |
| Summary: | The study of conformation in drug action can be approached from two directions, (i) that of the drug, and (ii) that of the receptor. Since the problem of elucidating the biologically active conformation of drug molecules has been extensively studied and is very well reviewed1,2, it should be equally productive to explore the conformational aspects of receptors.
Before a plausible model of conformational requirements at the receptor level can be developed, it is necessary to know something about the nature of the biologic receptors. Although structural details for specific receptors are generally unknown and a fascinating challenge for the medicinal chemist to study, the following considerations suggest that most receptors are lipoproteins with the ability to interact with specific substrates at their active sites. The known characteristics of receptors can be summarized as follows: a. Receptors can bind with a wide variety of drug molecules, suggesting a degree of conformational adaptability, a characteristic of proteins. b. Some receptors exhibit a relatively high degree of stereospecificity, a property shared by enzymes. c. Most receptor-like substances which have been isolated have been found to be proteolipid complexes, some of which may include phospholipids and prostaglandins if they are membrane-bound.
Its seems pertinent to mention that the problems involved in the isolation and characterization of drug receptors are formidable. The procedures employed in the extraction and purification of receptor-like substances are laborious and time-consuming, and the isolated material is, at best, only partially pure. Moreover, the results of drug-binding studies on such partially purified receptors are often equivocal. The hypothesis of induced conformational changes has been reviewed by several authors.5,6 For example, Koshland7,8,9 suggested that the active site of an enzyme does not need to be absolutely complementary to that of the substrate, but after interacting with it, induction of conformational changes can occur which might result in complementarity. Thus, it may be logical to assume on the basis of this hypothesis that in combining with an enzyme the substrate induces a change in its conformation. This results in an enzymatically active orientation of the catalytic groups. The biological response resulting from such a combination depends mainly upon the induction of an appropriate conformational change. |
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