THE RECEPTOR CONCEPT

It appears to the writer that the most important fact shown by a study of drag antagonisms is that it is impossible to explain the remarkable effects observed except by assuming that drags unite with receptors of a highly specific 

Clark s next step formed the basis of receptor theory by applying chemical laws to systems of infinitely greater complexity [4]. It is interesting to note the scientific atmosphere in which Clark published these ideas. The dominant ideas between 1895 and 1930 were based on theories such as the law of phasic variation essentially stating that certain phenomena occur frequently. Homeopathic theories like the Amdt-Schulz law and 

FIGURE 1.2 Schematic diagram of potential drag targets. Molecules can affect the function of numerous cellular components both in the cytosol and on the membrane surface. There are many families of receptors that traverse the cellular membrane and allow chemicals to communicate with the interior of the cell. 

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Dmg receptors are chemical entities which are typically, but not exclusively, small molecules that interact with cellular components, frequently at the plasma membrane level (1,2). There are many types of receptors heat, light, immune, hormone, ion channel, toxin, and vims are but a few that can excite a cell. The receptor concept can be appHed generally to signal recognition processes where a chemical or physical signal is recognized. This recognition is translated into response (Fig. 3) and the process can be seen as a flow of information. 

Today, it is accepted that Langley and Ehrlich deserve comparable recognition for the introduction of the receptor concept. In the same years, biochemists studying the relationship between substrate concentration and enzyme velocity had also come to think that enzyme molecules must possess an active site that discriminates among various substrates and inhibitors. As often happens, different strands of evidence had converged to point to a single conclusion. 

Limbird LE (2004) The receptor concept a continuing evolution. Mol Intervent 4(6) 326-336 National Institute on Drug Abuse (1987) The second triennial report to Congress From the Secretary, Department of Health and Human Services. National Institute on Drug Abuse, Rockville, MD... 

The receptor concept has important practical consequences for the development of drugs and for arriving at therapeutic decisions in clinical practice. These consequences form the basis for understanding the actions and clinical uses of drugs described in almost every chapter of this book. They may be briefly summarized as follows ... 

As Bourne and von Zastrow (2004) noted, the receptor concept has important practical consequences for the development of new drugs ... 

As for giving a symbolic landmark to drugs history at the beginning of the century, Paul Ehrlich (Institut fiir experi-mentelle Therapie, Frankfurt) (Figure 1.39) introduced, in 1900, the term receptor. The receptor concept as such, was in fact developed in the context of immunology. The drug receptor theory, in turn, would be later developed in Ehrlich s chemotherapy. 

The gradual evolution of the receptor concept as the basis for drug discovery over the past century has led to major advances in the understanding of biological systems and human disease states. 

Pharmacophore A pharmacophore is the spatial mutual orientation of atoms or groups of atoms assumed to be recognized by and interact with a receptor or the active site of a receptor. In conjunction with the receptor concept, the notion of a pharmacophore relates directly to the lock-and-key theory proposed by E. Fischer and P. Ehrlich around the beginning of the 20th century (Corpora non agunt nisi fixata). 

The receptor concept was initially greeted with skepticism. Attempts to isolate receptors as distinct substances failed. However, by the middle 1930s experiments were being performed on a quantitative basis, which began to dispel some of the doubts. Drug-recep-... 

The earlier doubts about the validity of the receptor concept may have been totally dispelled by the isolation from the electric eel, the fairly pure, nonenzymic protein receptor for acetylcholine. The properties, including kinetics, were close to those exhibited by the intact electroplax (the eel s electric organ) from which the receptor was isolated. Other receptors have since been isolated. 

Ariens, E. J., Rodriguez De Miranda, J. F., The Receptor Concept Recent Experimental and Theoretical Developments. In Recent Advances in Receptor Chemistry, Gualtieri, F., Giannella, M., Melchiore, C., Eds., Elsevier/North Holland Biomedical Press, New York, 1979, p. 1. 

The fact that apparently small changes in structures (specifically around the nitrogen atom) resulted in very specific and effective opiate antagonists, of course, added to the strength of the receptor concept. 

Early attempts to explain opiate analgesia by involvement of the receptor concept was followed by later demonstration of the existence of opiate receptors in the early 1970s in their characterization by sophisticated binding studies. This led to the realization that opiate receptors show considerable heterogeneity, and that they are not homogenous. They exist as subtypes with different properties and, in some cases, differ in anatomical loci. Initial work by Martin and co-workers (1976) with the spinal dog, utilizing morphine and certain... 

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