THEORIES OF DRUG RECEPTOR INTERACTION

THEORIES OF DRUG RECEPTOR INTERACTION

1. AGONIST, ANTAGONIST AND THEORIES OF DRUG RECEPTOR INTERACTION PRESENTED BY ABHISHEK GHARA 1 st YEAR M. PHARM DEPT. OF PHARMACEUTICAL CHEMISTRY

2. DRUG It is a natural or synthetic substances which has a physiological effects when administered into the body. RECEPTOR It is a specific binding site present on the cell surface made up of protein or nucleic acid where a ligand can bind and initiates a characteristic response.

3. CLASSIFICATION OF LIGANDS Ligands are classified by effects upon binding to the receptor

4. FORCES INVOLVED IN DRUG RECEPTOR INTERACTION Where k on is the rate constant for formation of the drug-receptor complex, which depends on the concentration of the drug and the receptor k off is the rate constant for breakdown of the complex, which depends on the concentration of the drug-receptor complex as well as other forces.

5. The biological activity of drug is related to its affinity for the receptor, i.e., the stability of the drug-receptor complex. This stability is commonly measured by how difficult is for the complex to dissociate, which is measured by its kd , the dissociation constant for the drug-receptor complex at equilibrium.

6. INTERACTIONS INVOLVED IN THE DRUG-RECEPTOR COMPLEX Ionic interactions Ion-dipole and dipole-dipole interactions, Hydrogen bonding Hydrophobic interactions Vander waals interactions Covalent bonding

7. 1. Occupation theory 2. Rate Theory 3. The induced-fit theory of enzyme-substrate interaction 4. Macromolecular perturbation theory 5. Activation-aggregation theory 6. Two state model of receptor activation THEORIES OF DRUG RECEPTOR INTERACTIONS

8. OCCUPATION THEORY Drugs act on binding sites and activate them, resulting in a biological response that is proportional to the amount of drug-receptor complex formed. The response ceases when this complex dissociates. Intensity of pharmacological effect is directly proportional to number of receptors occupied      D + R  DR  RESPONSE Response is proportional to the fraction of occupied receptors Maximal response occurs when all the receptors are occupied

9. RATE THEORY The response is proportional to the rate of drug-Receptor complex formation. Activation of receptors is proportional to the total number of encounters of a drug with its receptor. According to this view, the duration of Receptor occupation determines whether a molecule is agonist, partial agonist.

10. THE INDUCED-FIT THEORY According to this theory, binding produces a mutual plastic molding of both the ligand and the receptor as a dynamic process. The conformational change produced by the mutually induced fit in the receptor macromolecule is then translated into the biological effect, eliminating the rigid and obsolete “ lock and key” concept of earlier times Agonist induces conformational change – response Antagonist does not induce conformational change – no response Partial agonist induces partial conformational change-partial response

11. MACROMOLECULAR PERTURBATION THEORY Suggests that when a drug-receptor interaction occurs, one of two general types of Macromolecular perturbation is possible: a specific conformational perturbation leads to a biological response (Agonist), whereas a non specific conformational perturbation leads to no biological response (Antagonist)

12. ACTIVATION AGGREGATION THEORY Receptor is always in a state of dynamic equilibrium between activated form (Ro) and inactive form (To).

13. TWO-STATE (MULTI-STATE) RECEPTOR MODEL R and R* are in equilibrium (equilibrium constant L), which defines the basal activity of the receptor. Full agonists bind only to R* Partial agonists bind preferentially to R* Full inverse agonists bind only to R Partial inverse agonists bind preferentially to R

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