Lecture 2 — Drug–Receptor Binding and Introduction to Pharmacokinetics
1. Example of receptor antagonism: d-tubocurarine
• d-Tubocurarine is an antagonist of ACh at skeletal-muscle end-plate receptors.
• It competes with ACh for receptor occupancy, preventing ACh from producing its normal effect.
• The result is muscle relaxation, because ACh cannot induce and maintain contraction.
2. Studying receptor interactions
• Historically, researchers identified receptors by the relative selectivity of drug, neurotransmitter, and hormone effects.
• Mathematical analysis of dose–response relationships helped estimate dissociation constants, which describe the interaction of agonists or antagonists with their receptors.
3. Chemistry of drug–receptor binding
For a drug to trigger a biological response, its interaction with the receptor must be sufficiently strong and long-lasting. The lecture describes four types of interaction:
Covalent interactions
• Most drug–receptor interactions are reversible, but some alkylating agents, including anticancer nitrogen mustards, form relatively irreversible complexes.
• Long-lasting inhibition may be desirable in certain anticancer or antibiotic effects discussed in the lecture.
• Irreversible binding of environmental pollutants to cellular constituents may contribute to mutagenesis or carcinogenesis.
Ionic interactions
• Result from electrostatic attraction between oppositely charged groups.
• Receptors can contain ionizable groups such as carboxyl, hydroxyl, phosphoryl, and amino groups.
Hydrogen bonds and Van der Waals forces
• Multiple hydrogen bonds can stabilize drug–receptor binding while allowing reversibility.
• Hydrogen bonds contribute to protein and nucleic acid structure and to receptor selectivity.
• Van der Waals forces become meaningful at close distances and with complementary three-dimensional shapes.
• Small differences in molecular shape change the fit and strength of binding, contributing to structure–activity relationships.
Memorize from lecture: covalent ≈ 100, ionic ≈ 5, Van der Waals ≈ 0.5 kcal/mol.
4. Measuring receptor binding
Specific binding of radioactively labeled drugs can help estimate:
• Affinity: how strongly a drug binds to a receptor.
• Receptor density: the number of receptors per cell.
5. Second-messenger systems
• Some activated receptors initiate intracellular chains of events through second messengers.
• G proteins are guanine nucleotide-binding proteins. They bind GTP and can hydrolyze it to GDP.
• Whether an agonist acts on a cell first depends on whether the cell expresses the appropriate receptor.
• The nature of the response depends on the G protein coupled to the receptor, the kinase activated, and the proteins available for phosphorylation.
6. Introduction to pharmacokinetics
Pharmacokinetics = what the body does to a drug over time. Its main processes are:
• Absorption
• Distribution
• Metabolism
• Excretion
PK helps determine an appropriate drug formulation, dose, route of administration, and dosing frequency.
