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ENDOGENOUS DRUGUKE SUBSTANCES: IMPUCATIONS AND APPROACHES TO THEIR STUDY KENNETH A. GRUBER* In recent years there has been much interest in the isolation of endogenous substances which appear to be natural ligands for drug receptors in animals and man. This was a logical outcome of the discovery that many pharmacological agents exert their therapeutic effect by binding to sterospecific receptors. A natural extension of the "drugreceptor concept" was that endogenous ligands for these receptors should exist. The isolation of peptides with opiate properties [1] and the developing evidence that certain purines may function as endogenous benzodiazepines [2] reinforce this belief. For these two examples the primary structures of the endogenous compounds are unrelated to the primary structure of the drugs. The opioids were the first class of drugs for which an endogenous biological analog was demonstrated [I]. Consequently, the topographical analogies between opioid peptides (enkephalins) and opium alkaloids and their derivatives have been the most extensively investigated. Since the primary structure of the enkephalins is not obviously related to that ofthe opium alkaloids, several investigators have suggested possible conformations in which functional groups on the peptide would correspond spatially to areas ofthe morphine molecule known to be important for its analgesic activity [3]. The concept of purines as endogenous benzodiazepines is not as firmly established as that ofan endogenous morphine, primarily due to a Work supported by Research Career Development Award 1K04 HL 00804. The author thanks Drs. Vardaman M. Buckalew, Jr., and Ivan Davidson and MissJanice Whitaker for their help and encouragement during the preparation of this manuscript. This paper was submitted in the first Dwight J. Ingle Memorial Young Writers' competition for authors under 35.»Department of Medicine, Bowman Gray School of Medicine ofWake Forest University, Winston-Salem, North Carolina 27103.©1982 by The University of Chicago. AU rights reserved. 0031-5982/83/2601-0317$01.00 Perspectives in Biology and Mediane, 26, 1 · Autumn 1982 \ 51 much lower affinity ofpurines for the benzodiazepine receptor than that seen with the drug [4]. Nevertheless, receptors for benzodiazepines will bind hypoxanthine and its riboside inosine, and antibodies to diazepam will also recognize diese compounds [5]. In addition, the biological consequences associated with administration of these purines in vivo and in vitro, such as increasing the seizure latency induced by pentylenetetrazole and eliciting of specific neurotransmitter-like effects in primary cultures ofmouse spinal cord neurons, are consistent with their having diazepem-like activity [6, 7]. A major difficulty in the identification of endogenous druglike substances is the development of an appropriate assay for their detection. While bioassays are clearly the most pleasing from a mechanistic point of view, they offer a low degree of specificity and sensitivity. Receptor binding assays offer the major advantage of recognizing the threedimensional structure responsible for biological activity; however, this presupposes that the receptor complex for a drug can be isolated in a form which retains its in vivo specificity. In addition, nonspecific binding is a major problem in the analysis of receptor binding assays, with specific bindingbeing only a small fraction oftotal binding in some cases. The highly specific interaction of receptors with their ligand can, in some aspects, be compared with antigen-antibody binding. Both receptor and antibody binding sites recognize certain topographical features of the molecules they bind. However, antibodies are soluble proteins which exhibit low nonspecific binding. Ginzler, Levy, and Spector [8] were the first to propose that antibodies directed against abiologically active molecule might share common determinants for binding with its receptor. Such an antibody could function as a surrogate receptor, incorporating the best features of receptor binding (specificity for the biologically significant part of the molecule) with the simplicity of radioimmunoassays. Since most drugs are low molecular weight compounds, they do not usually elicit an immune reaction when injected into an experimental animal. Substances too small to stimulate an antibody reaction are called haptens. However, it is possible to produce antibodies to haptens if they are first conjugated to an antigenic protein. The basis ofthis approach to antihapten antibody production was thoroughly investigated by Landsteiner and co-workers, and the basic principles have been summarized [9]. Any attempt to produce antibodies to drugs which might function as surrogate receptors must...


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