Pharmacodynamics What Can The Drug Do To The Body Receptors and the Binding of Drug Molecules

The specificity and apparently high potency of certain chemicals, which makes it possible to use them as drugs, is provided by the existence of specific endogenous molecules on which the drugs can bind. These molecules, termed receptors, are proteins, and binding of a drug to a regulatory protein depends upon the structural conformity of both molecules. (There are a few exceptions from the protein rule: Some drugs act via binding to deoxyribonucleic acid (DNA) or lipid molecules.) Drugs are usually much smaller molecules than the regulatory proteins with which they interact. Ligands, a term referring to small molecules binding to a specific receptor, can be endogenous or exogenous: Morphine is an exogenous ligand for opioid receptors, whereas endorphins and enkephalins are the endogenous ligands. Figure A.1 demonstrates the specific binding of a drug to receptors, which can be quantified using radioactive isotopes. One can note that increasing the concentration of the drug increases its binding until saturation occurs because the number of available receptors is limited.

The term receptor is used liberally in physiology and pharmacology. In physiology receptor can mean a whole cell, in reference to detectors of sensory signals.

Figure A.1. Binding of drugs to specific receptors explains their potent physiological effects. This experiment demonstrates the binding of tritium-labeled raclopride to D2 dopamine receptors in cell membranes prepared from the corpus striatum of the rat. On abscissa, concentration of free radiolabeled raclopride in the assay medium. On ordinate, amount of radiolabeled raclopride specifically bound to the receptors. On inset: Scatchard plot (often used for evaluation of the maximal available number of receptors). (Courtesy of Dr. Ago Rinken, Department of Organic and Bioorganic Chemistry, Tartu University.)

The most common meaning of the word, and the most universally accepted one by pharmacologists, is a protein molecule that recognizes endogenous signal molecules and mediates their effect to intracellular executive mechanisms. Such an example is provided in Fig. A.1, where binding of a drug to receptors that physiologically mediate the effect of the neurotransmitter dopamine is presented. Yet in pharmacology any molecule serving as a drug target, even an enzyme or transporter, can be termed a drug receptor. Furthermore, sometimes pharmacologists speak of silent receptors or acceptors, which are in essence any molecules binding a drug molecule without any resultant immediate physiological effect, such as serum proteins.

In the case of the so-called drug receptors, some drugs form covalent bonds with the receptive substance. First-generation monoamine oxidase inhibitors such as iproni-azide serve as an example of this type of a drug-receptor interaction. Because covalent bonds are usually irreversible at body temperature, the enzyme in our example becomes nonfunctional permanently, and the effect of the drug lasts until a sufficient amount of a new enzyme protein is synthesized. Most drug-receptor complexes make use of noncovalent bonds, which support reversible interactions. The reversibility of ligand binding first presented in Fig. A.1 is shown in Fig. A.2: Various substances, including dopamine, the endogenous ligand, are able to compete with the radiolabeled drug and displace it from the receptors depending upon their concentration. Noncovalent bonds that establish reversible binding include ionic bonds, hydrogen bonds, van der Waals bonds, and spatial arrangements of hydrophobic groups of receptors and drugs. These bonds are relatively weak and require close approximation of surfaces for formation of a ligand-receptor complex. This makes the three-dimensional structure

Figure A.2. In the case of reversible binding, drugs compete for the binding sites. This experiment demonstrates inhibition of [3H]raclopride binding to D2 dopamine receptors in rat striatal membranes by three synthetic drugs and dopamine, the endogenous ligand. On abscissa, concentration of competing substances added to the assay. On ordinate, the proportion of maximal specific binding of raclopride to the receptors. (Courtesy of Dr. Ago Rinken, Department of Organic and Bioorganic Chemistry, Tartu University.)

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of receptors and drug molecules extremely important for any functional interaction. As a consequence, the structure-activity relationship, which forms one cornerstone in pharmacology, appears puzzling to a novice: Chemical structures that seem very similar may have very different receptor binding profiles, whereas structures with fairly different appearances may share enough three-dimensional similarity to interact with a common receptor. Thus, a drug-receptor complex is formed when the spatial arrangements of their respective molecules fit like a key in the lock, but not all aspects of the three-dimensional structures are critical for such a fit.

An important aspect in the key and lock concept of spatial compatibility is the conclusion that there must be stereospecificity in the action of drugs. Indeed, many drug molecules contain an asymmetrical carbon atom, which makes it possible to have two different molecules as mirror images of each other, termed stereoisomers. Unlike actual mirror images that we can easily recognize as the original faces, receptors do not recognize mirror images of drugs, which renders them biologically inactive. As a matter of fact, the mechanism of action of psychopharmacological drugs is often studied by comparing the effect of active drugs with their stereoisomers. Stereospecificity of effect—which means that only one of the mirror image molecules is biologically active—is suggestive of a receptor-mediated action.

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