Drug-Receptor Interaction Theories

Drug-Receptor Interaction Theories

  • The drug and receptor interaction has been explained by several theories, each contributing unique insights into how drugs interact with receptors in the body (LOMIRMTT).

1. Lock and Key Theory

  • Author: Emil Fischer (1894)

  • Description:

    • This oldest theory compares the receptor to a lock and the drug to a key.

    • The receptor has a specific configuration (the lock) that only a drug with a complementary shape (the key) can bind to.

    • If there are any changes in the drug's structure, even slight ones, it will not fit the receptor and therefore cannot effect a biological response.

2. Occupancy Theory

  • Author: A J Clark (1926), A V Hill (1909)

  • Description:

    • This theory quantifies drug effect by indicating that the magnitude of the response is directly proportional to the number of drug molecules bound to the receptors.

    • The maximum biological response occurs when all receptors are occupied at equilibrium, highlighting the importance of receptor availability in drug efficacy.

3. Modified Occupancy Theory

  • Authors: Ariens (1954), Stephenson (1956)

  • Description:

    • Retains the assumption that tissue response relates to the number of occupied receptors but proposes that the drug-receptor interaction occurs in two phases:

      • (1) the combination of drug and receptor (affinity) and;

      • (2) the resulting biological effect (efficacy or intrinsic activity).

4. Induced-fit Theory

  • Authors: Daniel E. Koshland, Jr. (1958)

  • Description:

    • Contrary to the Lock and Key Theory where the receptor is rigid, this theory posits that the receptor is partially flexible.

    • When a drug binds to the receptor, it induces a conformational change in the receptor's structure, allowing the drug to fit more effectively, which can enhance or alter its effectiveness.

5. Rate Theory

  • Authors: Craxatto and Paton (1961)

  • Description:

    • It states that the interaction between drug and receptor is proportional on the rate of drug-receptor combination.

    • Agonists typically exhibit rapid rates of association and dissociation, while antagonists show a high association rate but low dissociation rate, which impacts their overall action in the body.

6. Macromolecular Perturbation Theory

  • Author: Belleau (1964)

  • Description:

    • This theory explains the interaction between small drug molecules and large macromolecules (receptors).

    • It suggests that an agonist will lead to a specific conformational change (perturbation) in the receptor, whereas an antagonist's interaction results in a non-specific conformational perturbation, affecting how they elicit biological responses.

7. Two State Receptor Theory

  • Authors: Black and Leff (1983)

  • Description:

    • This theory proposes that binding of a drug to a receptor induces a transition from an inactive to an active state of the receptor.

    • Once activated, the receptor can produce a significant biological effect, underscoring the dynamic nature of receptor activation.

8. Ternary Complex Model

  • Authors: Samama et al. (1993)

  • Description:

    • This theory introduces a three-component interaction involving the drug, the receptor, and a G-protein, establishing a new equilibrium that goes beyond the typical drug-receptor interaction model.

    • It highlights that the efficacy of a drug is influenced not just by its binding to the receptor, but also by its interactions with other components within the “native receptor ensemble”, particularly in how receptors move laterally in the cell membrane when activated by agonists.