Receptor Theories

Receptor:

Most drugs and chemicals (neurotransmitter) exert their potent and specific action in the body by forming a bond with cellular constituent’s term as receptor.

The existence of cellular receptor for a drug can be deduced from following:

• Relationship between structure and activity in homologous series of compounds.
• Agonist-Antagonists pair’s quantitative studies.
• Radioactive drug binding with cell membrane and isolated receptor.

                                                              Receptor consequences:

1.      Receptor largely determines the quantitative between drug and pharmacological effect:

The affinity of a receptor towards drug determines the drug concentration required to produce number of complexes between drug and its receptors.

2.      Receptors are responsible for selectivity of drug action:

The affinity of a drug to bind to a particular receptor among the vast array of chemically different binding sites depends upon the size, shape and charge of a drug.

3.      Receptor mediates the action of pharmacologic agonist and antagonists:

There are different types of substances, some are those which regulate the function of receptor and some down regulates.

The receptor functioning these substances are categorized as

• Agonist
• Antagonist

è Agonist:

Some drugs and many natural ligands such as neurotransmitters regulate the function of receptor, these are known as agonist.

è Antagonist:

Some antagonist also acts on receptor and deactivate the receptor means they interfere with the normal functions of receptor.

                                                      Nature of a receptor

Most of receptors are protein presumably because the structure of polypeptide provides the necessary diversity and specifity of shape, size and electric charge for a receptor.

Receptor are present on different sites some are embedded in plasma membrane while other in cytoplasm or nucleus of a cell to which one or more signaling molecule get attached.

Any substance which binds to the receptor is termed as ligand. Ligand can be a peptide neurotransmitter, hormone, toxin or any pharmaceutical drug.

Receptor are sensitive in nature it recognize and binds only to certain ligands shapes (like lock and key or hand in a glove where lock represents receptor while key denotes a ligand) when ligand binds to a receptor it determines that either receptor should be activated or inhibited.

When ligand binds to the receptor, it stabilizes the conformation of a receptor (three dimensional shapes). These changes which were induced by ligand result in cellular changes which constitute the biological activity of ligand.

Structure

This is the structure of a transmembrane receptor.

There is a great diversity in the structure of a receptor and it can be a widely classified in the following categories.

1. Peripheral membrane proteins
2. Transmembrane proteins
   1. G-coupled protein receptor
   2. Ligand dated ion channels
   3. Voltage gated ion channels
   4. Soluble globular protein

• Nuclear receptor

                                                        Techniques for structure study

There are different types of techniques which are used to study the structure and even functions of a receptor. These biophysical methods are as follows.

• X-ray crystallography
• NMR
• Dual polarization interferonmenrtry
• Circular dichrosim

To understand the mechanism of an action of a receptor computer stimulation of dynamic behavior of receptor has been used.

                                    Receptor Theories

Receptor theory is a receptor model application to explain the behavior of a drug. Contemporary scientist take is as a “given” that biological substance such as hormones and drugs exert their effect via interaction with the specific receptor in a manner analogous to the interaction of a substrates to the enzyme. This dogma was not always self-evident, but evolves from remarkable insights of early scientist exploring a number of fundamental living processes.

From many years, pharmacological receptor models proceeded accurate knowledge of receptor. The receptor concept was first proposed by Langley in 1878 and was used extensively by Paul Ehrlich in his studies on chemotherapy. Many scientists have contributed for the evolution of the receptor concept.

Receptor theories proposed by scientists and their work is given as follows.

                                                  CLAUDE BERNARD’S WORK:

Although Claude Bernard never used the term receptor, he pioneered a pattern of scientific investigation that permitted clarification of the specificity and selectivity of a drug action, particularly in regard to the locus of a drug effect.

Bernard simply wanted to know that how the arrow poison curare worked. It was effective when administered by an arrow, but interestingly was ineffective when taken by mouth. His early studies explain the importance of the route of administration of this drug for it lethal effects by demonstrating that although curare was unaltered functionally by saliva, gastric juice, bile or pancreatic juice. It was not observed by the GIT, This accounting for its harmlessness when swallowed. Bernard wanted to understand just how curare affected its lethal paralysis. It was his impression from general observation that curare did not effect the sensory nerves but instead altered motor nerve function.

By an engineers group of experiments, he determined that curare blocked the ability of motor nerve to control muscles contraction. Early experiment injected curare unclear the skin on the back of the frog, the frog showed fever and fewer reflex, movements. If he skinned the hind leg of the frog that had been exposed to curare and isolated the lumber nerve, he could produce the no contraction of leg muscles by stimulating the nerves electrically, whereas he could produce violent contraction if the same electric stimuli were applied directly to the muscle. Bernard concluded from these experiments that muscles contractility is distinct from nervous system that produces it and that curare removes the neural control of muscle function. He also concluded that curare selectively interferes with motor nerves function and leaves sensory nerve functions. In fact, based this conclusion on observation from the following experiment:

• He ligated one of the hind limbs of frog in such  a way that nerve input was intact but circulation was blocked, when curare was administered to the frog, the muscles of the ligated limb was not paralyzed , Indicating that curare was not been delivered to this limb as a result of cutting of its blood circulation. Pinching the frog in protein of body where the curare had penetrated elicited reflex movements in the unparalyzed, ligated limb. Thus although curare had paralyzed the muscle in certain portion of the body, it had not affected sensory nerve function in these paralyzed portion of the body and this intact function could still evoke the muscular contraction in the protected limb.

Bernard did not talk about receptor, but he did demonstrate that the functional efficacy of a drug depends upon its access to a particular location.

As a result of his finding Bernard encouraged investigators, not to focus studies of a drug on organ system for e.g., nervous system or the muscular system.

                                                           WORK OF J.N LANGLEY:

The receptor concept was first proposed by JN Langley in 1878.

While investigating the apposing action of atropine and pilocarpine on salivary secretions, Langley suspected the presence of some substance in the nerve ending or glad with which the drug combines.

Until some definite conclusion as to the point of action of the poison is arrived at it is not worth while to theories much on their mode of action but there are some substances or substance in the verve ending or gland cell with which both atropine and pilocarpine are capable of forming compounds . On this assumption then the atropine or pilocarpine compounds are formed according to the some law of which their relative mass and chemical affinity for the substances are important factors .In the analogous case with inorganic substances, Other thing being equal these are the sole factors for the substances to take the simplest case, when there are two substances I-e atropine and pilocarpine and both of those substances are able to form a complex with the receptive substances compounds of pilocarpine and receptive substances , atropine and receptive substances are formed , quantity of which depends upon the relative masses of pilocarpine and atropine present and their relative chemical affinity towards receptive substances. But suppose 2mgs of atropine and 30 mgs of pilocarpine to be injected but there was no secretion seen, it means pilocarpine was not able to form a compound with a receptive substance. Since this receptive substance is essential to show biological action.

Langley coined the term receptor for this accessory receptive substance. He was first to give concept that some accessory receptive substances are present to which drug bound to show its relative biological action.

                                                               ERHLICH WORK:

The receptor concept is generally attributed to Paul Erhlich although the word receptor was coined by one of Erhlich’s contemporaries J.N Langley. Erhlich was remarkable individual whose scientific carrier spanned several biomedical disciplines. One overriding principal was common to all his investigation was selectively.

Erhlich’s earlier work involved the distribution of lead in the body and in particular, its accumulation in the central nervous system. He had been inspired by a publication of Heuber on lead poisoning which demonstrated that there were significant difference in the lead amount found in various organ of animals to dilute solution of lead and organ show same lead uptake as in vivo. In Erhlich continuation of these studies, he realized that it was impossible to use microscope to determine the basis of this differential selectivity of lead uptake in different tissues so he used staining of tissues by various dyes, as this could be easily detected.

Erhlich’s study on dye distribution originated the concept of vital staining and was morphological distinction of leukocytes as acidophilic, basophilic and neutrophilic is still in practice.

Erhlich most acclaimed studies were his subsequent experiments in immunochemistry. By neutralizing the activity of toxins following incubation of toxins with anti toxins in test tube. He demonstrated that Ag-Ab interactions are direct chemical encounter and not generalized phenomena which require biological process. From these observations he develops “side chain theories”, to explain the chemical nature of immune response. He described that Ag posses two active areas.

• Haptophore
• Toxophile

He postulated that mammalian cell posses “side chains” that are complementary to the certain chemical group on Hatophore domain of the Ag. This side chain + haptophore interaction provides “Toxophile” portion access to the cell that posses appropriate side chain.  His side chain theory was able to explain the observation concerning with the uptake f lead in the central nervous system and principal governing vital staining of living cell. Inherent in Ehrlich’s side chain theory was providing he concept of specific cell receptor as the basis for targeting bioactive agent (drug and neurotransmitter) to the appropriate cell for response.

Erhlich then turned his attention from macromolecules to micro molecules in a series of investigation which earned him the recognition “Father of chemotherapy”. He believed that pharmaceutical industry could produce the number of small molecules such as analgesic, anesthetics which appears least functionally to differentiate among various tissues in human beings.

Erhlich conceived, Receptors are group of protoplasmic macromolecules with which drug combines reversibly or irreversibly.

                                                Current Concept:

According to current concept, there are several types of drug receptors. Some are on the external surface of the plasma membrane or target cell for example receptors which interact with peptide hormones and releasing factor or with drugs that mimic or block the actions of autonomic mediators such as catecholamine. These receptors are for the most part, coupled with second messengers. Other receptors are located in the cytoplasm of target cell, for example, those that combine with drug that mimic or block the actions of steroid hormones with these the drug-receptor combination is translocated to the nucleus where it may regulate expression of a gene and there by the concentration of a specific mRNA and ultimately protein synthesis, still other receptors such as those for thyroid hormones are in the nucleus.

Written  By Hummara Akram

University of Balochistan

References:

1. Basic and clinical pharmacology by Bertram G katzung
2. Goth’s medical pharmacology by Clarke , Brater, Johnson
3. Cell surface receptor by Lee-E limbird.