Concept of Receptors

Some chemicals, such as strong aids and bases, exert their toxic action in a nonspecific way simply by denaturing protein and dissolving the tissue. Such lesions are referred to as chemical bums. In most cases, however, toxins act by interacting with specific components of the tissue, thus perturbing normal metabolism. Early in the twentieth century Paul Ehrlich (Ehrlich, 1913) proposed the concept of specific receptors. He posmlated that a chemical, in order to exert biological action, must reach a specific target area and fit into a receptor site. 

Many receptors have been identified in all cases they are proteins. Some of the proteins have enzymatic activity. Eor instance, dihydrofolate reductase is a receptor for antifolates and acetylcholine esterase is a receptor for organophosphates. Some receptors serve as transport vehicles across the cellular membranes, as is the case with the receptors for steroid hormones (Baxter and Eorsham, 1972). Specific receptors may be confined to certain tissues or may be distributed among all the cells of an organism. 

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Long introduces ether as an anesthetic Locock accidentally discovers bromides as anticonvulsants Lister pioneers use of phenol as a surgical antiseptic Liebreich discovers hypnotic effects of chloral hydrate Strieker uncovers analgesic properties of salicylic acid Guthzeit and Conrad synthesize a series of barbiturates Erlich pioneers concepts of receptor and chemotherapy ... 

In understanding the kinds of processes by which toxic substances harm an organism, it is important to understand the concept of receptors.9 Here a receptor is taken to mean a biochemical entity that interacts with a toxicant to produce some sort of toxic effect. Generally receptors are macromolecules, such as proteins, nucleic acids, or phospholipids of cell membranes, inside or on the surface of cells. In the context of toxicant-receptor interactions, the substance that interacts with a receptor is called a ligand. Ligands are normally relatively small molecules. They may be endogenous, such as hormone molecules, but in discussions of toxicity are normally regarded as xenobiotic materials. 

Receptors, like all proteins, are known to spontaneously adopt a variety of conformations, and current concepts of receptor function (e.g., the extended and cubic ternary complex models) are based on the allosteric transitions between multiple conformational states. Some of these conformations are called active because they are able to interact with cellular signal transduction mechanisms (and are the basis of constitutive receptor activity ). If one assumes that different receptor conformations might present different intracellular portions of a... 

The concept of receptors is credited to the independent work of Paul Ehrlich (1845-1915) and J. N. Langley (1852-1926). With Ehrlich, the concept appeared to originate from his immunochemical studies on antibody-antigen interactions. Based on the high degree of specificity of antibodies for antigens, Ehrlich postulated the existence of stereospecific, complementary sites on the two molecules. Similar... 

Evolving Concepts of Receptor-Induced Functional Changes... 

The pharmacological concept of receptors, based upon the observation of rigid structure-activity relationships, stereospecificity, and the observation of maximal pharmacological responses goes back to the turn of the century. More than a hundred years ago, Fischer [1] proposed the lock-and-key model for the enzyme-glycoside system. Later, Langley [2] and Ehrlich [3] further developed this model which can be applied to receptors as well. 

The concepts of receptor and pharmacophore play a basic role in the alignment of molecules in - grid-based QSAR techniques. 

FIGURE 1.2 A sampling of the heterogeneous physiological and pharmacological response to the hormone epinephrine. The concept of receptors links these diverse effects to a single control point, namely the P-adrenoceptor. 

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