ReceptorsReceptors Dr. Syed Atif Abbas

RECEPTOR?

Definition Definition A molecular structure within a cell or on the surface characterized by:

1. Selective binding of a specific substance 2. A specific physiological effect that

accompanies the binding e.g membrane receptors for hormones, neurotransmitters and antigen.

A sensory nerve terminal that responds to stimuli of various kind e.g photoreceptors, barroreceptors etc.

IntroductionIntroductionThe development of the concept that receptors mediated the effect of drugs was based primarily upon a series of observations made during the late nineteenth and early twentieth centuries. These observations correlated chemical structure with biological activity, and demonstrated the fact that relatively small amounts of drug can elicit an effect.

One of the earliest proposals associating chemical structure with function was that of J. Blake in 1848. Blake suggested that the biological activity of certain metallic salts was due to their metallic component, rather than the complex in its entirety (e.g., the lead moiety in lead acetate or lead nitrate). This important concept received theoretical support in 1884 when Arrhenius introduced his theory of electrolytic dissociation, whereby salts dissolved in water become dissociated into oppositely charged ions.

The concept of drugs acting upon receptors is generally credited to John Langley, who alluded to their existence in 1878. While studying the antagonistic effect of atropine against pilocarpine-induced salivation, Langley wrote "that there is some substance or substances in the nerve endings or gland cells with which both atropine and pilocarpine are capable of forming compounds."

In 1905 Langley subsequently referred to this factor as "receptive substance." Despite this observation, the specific word "receptor" was not introduced into the medical literature until the turn of the century by Paul Ehrlich.

Ehrlich believed that a drug could have a therapeutic effect only if it has "the right sort of affinity." He specifically wrote "that combining group of the protoplasmic molecule to which the introduced group is anchored will hereafter be termed receptor." (It might be appropriate at this point to give credit to the Italian Amedo Avogadro (1776-1856) who coined the term molecules, from the Latin for "little masses".)

THE NATURE OF RECEPTORSTHE NATURE OF RECEPTORSReceptors are regulatory macromolecules, mostly proteins, though nucleic acids may also serve as receptors. They are no longer hypothetical. Hundreds of receptor proteins have been isolated, purified, cloned and their primary amino acid sequence has been worked out.

Many drugs act upon physiological receptors which mediate responses to transmitters, hormones, autacoids and other endogenous mediators; examples are cholinergic, adrenergic, histaminergic, steroid, prostaglandin and other receptors.

In addition, now some truly drug receptors have been described for which there are no known physiological ligands, e.g. benzodiazepine receptor, cardiac glycoside receptor, thiazide receptor.

Proteins, glycoproteins, proteolipids, and associated proteinaceous species appear to be particularly suited to act as receptors because they can assume three-dimensional configurations, the three-dimensional shape being the net result of primary, secondary, and tertiary structures. Three dimensionality requires that drugs, or any binding ligand, achieve binding specificity, referred to as "induced fit."

If the drug is an active one, the result of this binding is believed to be a conformational change in the receptor, with subsequent modification of membrane permeability or activation of intracellular enzymes.

The concept of a "lock and key" relationship between drug and receptor is based upon the analogous hypothesis of the German chemist and enzymologist Emil Fischer, who originally developed the theory in relation to the interaction between enzymes and substrates.

In 1895 Fischer wrote that an enzyme's specific effect might be explained "by assuming that the intimate contact between the molecules necessary for the release of the chemical reaction is possible only with similar geometrical configurations. To use a picture, I would say that the enzyme and the substrate must fit together like lock and key."

This lock and key relationship implies extreme precision in the interaction, since extra or improperly placed atoms in the drug, like an additional tooth on a key, can exclude its binding. Failure to achieve "induced fit," therefore, precludes optimal conformational change in the receptor.

The specificity inherent in achieving appropriate geometrical configurations between ligand (i.e., drug) and receptor can extend to stereoisomerism. For example, there are many drugs whose chemical structure contains an asymmetric carbon atom and can thus exist as mirror-image isomers; asymmetry is possible only if all four valences of carbon are utilized by different groups.

These asymmetric carbon atoms are often referred to as chiral centers or, conversely, centers of chirality. An example of an optical isomer is the antitussive drug dextromethorphan (found in many OTC cough and cold preparations), which is the d isomer of the codeine analog levorphanol. However, unlike the l isomer levorphanol, dextromethorphan has no analgesic or addictive properties and does not act through opioid receptors.

During the 1960s and 1970s, receptor proteins, primarily membranous in nature, were isolated and the amino acid sequences of various receptor subunits were determined. In the past two decades complete amino acid sequences of receptors have been determined, and also been successfully cloned.

CHEMICAL BONDSCHEMICAL BONDSIf most drugs achieve their effects via interaction with a receptor, then by what chemical binding force is this achieved? Ehrlich recognized very early that the combining forces must be very loose.

He wrote in 1900: "If alkaloids, aromatic amines, antipyretics or aniline dyes be introduced into the animal body, it is a very easy matter, by means of water, alcohol or acetone, to remove all of these substances quickly and easily from the tissues."

This is the reason why isolated organ tissue baths containing smooth muscle preparations, such as the guinea pig ileum, can be used experimentally for the sequential assessment of drug activity, since "wash-out" phases can restore the tissue essentially to its original condition.

The four most favorable forces in chemical bond formation between ligand and receptor in pharmacology are

(1) ionic bonds (i.e., electrostatic);(2) hydrogen bonds(3) van der Waals forces(4) covalent bonds.

Ionic bondsIonic bondsThese are the principal electrostatic bonds that are formed between two ions of opposite charge (e.g., Na+ and Cl-) in which the atom lacks or has surplus electrons. The extent to which ionic bonds may be formed depends on the degree of ionization of groups that form cations (e.g., amino groups) and groups that form anions (e.g., carboxyl groups).

Hydrogen bondsHydrogen bondsThe hydrogen nucleus is strongly electropositive, being essentially a bare proton. This high concentration of electropositivity enables the hydrogen atom to act as a bond between two electronegative atoms. Individually, hydrogen bonds are weak, but collectively they can significantly stabilize the association of a drug with its receptor.

van der Waals forcesvan der Waals forcesThese are the most common of all attractions between atoms, van der Waals forces are the result of the formation of "induced dipoles" when atoms of different electronegativity are bonded together. The intermolecular attraction arises from the fluctuations of charge in two atoms or molecules that are close together.

Covalent bondsCovalent bondsThe covalent bond, is the most tenacious type of chemical bond since it involves the mutual sharing of orbital electrons. It is the type of bond that holds organic compounds such as proteins, carbohydrates, and lipids together. Fortunately, for these important biochemical entities, it normally does not lend itself to easy reversibility.

Silent receptorsSilent receptors These are sites which bind specific drugs but no pharmacological response is elicited. They are better called drug acceptors or sites of loss, e.g. plasma proteins which have binding sites for many drugs. To avoid confusion, the term receptor should be restricted to those binding sites which are capable of generating a response.

Receptor ClassesReceptor Classes