The Receptor Concept_Sachin Kumbhoje


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The Receptor Concept:

The Receptor Concept By Sachin R. Kumbhoje

Learning Objectives::

Learning Objectives: Understand the theoretical basis of drug-receptor interactions. Understand the determinants and types of responses to drug-receptor interactions. Know the four major families of receptors. Define potency and efficacy.

Outline of Presentation 1. Definition and History of Receptor 2. Affinity and Intrinsic Activity 3. Receptor & Biological Response 4. Drug-Receptor Interaction 5. Receptor Theories:

Outline of Presentation 1. Definition and History of Receptor 2. Affinity and Intrinsic Activity 3. Receptor & Biological Response 4. Drug-Receptor Interaction 5. Receptor Theories


HOW DRUGS ACT l. Enzyme Inhibition: Drugs act within the cell by modifying normal biochemical reactions. Enzyme inhibition may be reversible or non reversible; competitive or non-competitive. Antimetabolites may be used which mimic natural metabolites. Gene functions may be suppressed. 2. Drug-Receptor Interaction: Drugs act on the cell membrane by physical and/or chemical interactions- usually through specific drug receptor sites known to be located on the membrane. Some receptor sites have been identified with specific parts of proteins and nucleic acids. In most cases, the chemical nature of the receptor site remains obscure. 3. Non-specific Interactions: Drugs act exclusively by physical means outside of cells. These sites include external surfaces of skin and gastro-intestinal tract. Drugs also act outside of cell membranes by chemical interactions. Neutralization of stomach acid by antacids is a good Example.

What is a Receptor?:

What is a Receptor? To a neuroscientist A protein that binds a neurotransmitter/modulator To a cell biologist or biochemist A protein that binds a small molecule A protein that binds another protein A nucleic acid that binds a protein To a toxicologist A macromolecule that binds a toxicant Etc.


History 1878 : John N. Langley British Physiologist Study of Antagonism effect of Atropine and Pilocarpine 1907: Paul Ehlrich Pioneer of Chemotherapy and Immunochemistry

Receptor Concept:

Receptor Concept Enzymes are one major target for drugs. Receptors are another. Drugs which interact with receptors are amongst the most important in medicine and provide treatment for ailments such as pain, depression, Parkinson's disease, psychosis, heart failure, asthma, and many other problems. What are these receptors and what do they do? A receptor is a protein molecule embedded within the cell membrane with part of its structure facing the outside of the cell. This area is known as the binding site and is analogous to the active site of an enzyme. When the chemical messenger fits into this site, it 'switches on' the receptor molecule and a message is received

Definition of Terms:

Definition of Terms Receptors – are chemicals which binds to the drug to exert a pharmacologic effect. Formula: D + R = D-R ------ Drug Response A Receptor is analogous to a switch in that it has two configurations: “ON” and “OFF ”


Definitions Affinity : The ability of a drug to bind to the receptor Intrinsic activity (= “efficacy”): The ability of a drug to elicit its Pharmacological effect Intrinsic efficacy (outmoded): the property of how a ligand causes biological responses via a single receptor (hence a property of a drug). Potency : How much of a ligand is needed to cause a measured change (usually functional).

Definition of Terms:

Definition of Terms Affinity – allows the agonist to bind to receptors. Intrinsic Activity – allows the bound agonist to activate or turn on its receptor function.

Drug-Receptor Interactions:

Drug-Receptor Interactions Ligand + Receptor Ligand-Receptor Complex Response(s)

Bimolecular Interactions: Foundation of Most Studies:

Bimolecular Interactions: Foundation of Most Studies Rearrange that equation to define the equilibrium dissociation constant K D . At equilibrium: Ligand + Receptor Ligand-Receptor Complex Response(s)

Factors Affecting Drug Receptor Interaction :

Factors Affecting Drug Receptor Interaction Isosterism Steric Features of Drug Optical Isomers and Biological activity Conformational Factors


Types of Receptor

Classification of a drug based on drug-receptor interactions::

Classification of a drug based on drug-receptor interactions: Agonist: Drug that binds to receptors and initiates a cellular response; has good affinity as well as good Intrinsic activity/efficacy . Agonists promote the active state. Antagonist: drug that binds to receptors but cannot initiate a cellular response, but prevent agonists from producing a response; Good affinity, but no Intrinsic activity/efficacy . Antagonists maintain the active-inactive equilibrium.


cont. Partial agonists: Drug that, no matter how high the dose, cannot produce a full response. Equal/less affinity than agonist as well as moderate intrinsic activity Inverse agonist: Drug that binds to a receptor to produce an effect opposite that of an agonist. Stabilizes receptors in the inactive state.


Antagonists Antagonists exhibit affinity for the receptor but do not have intrinsic activity at the receptor. An antagonist that binds to the receptor in a reversible mass-action manner is referred to as a competitive antagonist. Because the antagonist does not have intrinsic activity, once it binds to the receptor, it blocks binding of agonists to the receptor. A key point about competitive antagonists is that like agonists, they bind in a reversible manner. This has important implications regarding the effect competitive antagonists have on the configuration of the dose-response curve of agonists


Dose-Response Curves Dose-response relationships are a common way to portray data in both basic and clinical science. For example, a clinical study may examine the effect of increasing amounts of an analgesic on pain threshold. To present the data, the concentration of the drug would be plotted on the x-axis and the effect on pain threshold would be presented on the y-axis. A plot of drug concentration ([D]) versus effect (E/ Emax ) (or for that matter DR/RT) is a rectangular hyperbola. Notice how the drug effect reaches a plateau or maximum. This is because there are a finite number of receptors. Hence, the response must eventually reach a maximum. However, the hyperbolic plot is a cumbersome graph because drug concentrations often vary over 100 to 1000-fold. This necessitates a long X-axis. To overcome this problem, the log of the drug concentration is plotted versus the effect. A plot of the log of [D] versus E/ Emax is a sigmoid curve.


As illustrated below, the position and shape of the log-dose response curve is dependent on the affinity of the ligand for the receptor and its intrinsic activity. Affinity determines the position of the dose-response curve on the X-axis, while intrinsic activity affects the magnitude of the response.


In most physiological systems in which drugs will be administered, the relationship between receptor occupancy and response is not linear but some unknown function f of receptor occupancy. In the graph, this unknown function is presented as being hyperbolic. As the graph depicts in this type of system, all receptors do not have to be occupied to produce a full response. Because of this hyperbolic relationship between occupancy and response, maximal responses are elicited at less than maximal receptor occupancy. A certain number of receptors are "spare." Spare receptors are receptors which exist in excess of those required to produce a full effect. There is nothing different about spare receptors. They are not hidden or in any way different from other receptors.

Forces involved in Drug Receptor Interaction :

Forces involved in Drug Receptor Interaction Covalent Bonding: Electrostatic Bonding: Charge Transfer Complex: Hydrophobic Forces: Van der walls or London Dispersion Forces:

Drug-Receptor Theories:

Drug-Receptor Theories Theory of Law of Mass Action Hypothesis of Clark “ The Pharmacologic effect of the drug depends on the percentage of the receptors occupied” If receptors are occupied, maximum effect is obtained. Chemical binding follow the Law of Mass Action.

Drug-Receptor Theories:

Drug-Receptor Theories Occupation Theory Hypothesis of Ariens and Stephenson “ Effectiveness of a drug lasts as long as the receptor is occupied. Many substance possess different effect , some have high affinity for the receptor, some have low affinity and some are not effective, and those ineffective substances block or inhibit the receptor.”

Drug-Receptor Theories:

Drug-Receptor Theories Rate Theory Hypothesis of Paton “ Effectiveness of a drug does not depend on the actual occupation of the receptor but by obtaining proper stimulus”

Drug-Receptor Theories:

Drug-Receptor Theories Intrinsic Activity Lock and Key Hypothesis “ The drug molecule must fit into the receptor like a key fits into the lock”

Drug-Receptor Theories:

Drug-Receptor Theories Macromolecular Perturbation Theory Belleau Hypothesis “ The interaction of small molecules of drug or substrate with macromolecule (such as protein or drug receptor) may lead either to Specific Conformational Perturbations (SCP) or Non-Specific Conformational Perturbations (NSCP)” If SCP: Agonist action If NSCP: Antagonist action

Drug-Receptor Theories:

Drug-Receptor Theories Activation-Aggregation Theory Karlin and Changeux Hypothesis “ Even in the absence of drug, a receptor is in a state of dynamic equilibrium between activated form (which is responsible for the biological action) and inactive form” Agonist shift the equlillibrium to activated form Antagonist bind to the inactive form Partial Agonist bind to both conformations

Spare receptors:

Spare receptors Some tissues have more receptors than are necessary to produce a maximal response. Dependent on tissue, measure of response and intrinsic efficacy of the drug. The binding sites of any active sites that can retain the drug molecules, without initiating biological response are silent receptors. E.g.: Adsorption Sites of Plasma Proteins Silent receptors


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