Drug-Receptor Interactions

Question 1

What factors determine complementarity of a drug to its receptor?

Answer 1

• Hydrophobicity
• Ionisation state (pKa)
• Conformation
• Stereochemistry (D/L isomer).

Question 2

What are the 6 Drug-Receptor interaction classifications?

Answer 2

1. Transmembrane ion channels
2. Transmembrane receptors coupled with intracellular G proteins
3. Transmembrane receptors with linked enzymatic domains
4. Intracellular receptors, including enzymes, signal transduction molecules, transcription factors, structural proteins, and nucleic acids
5. Extracellular targets
6. Cell surface adhesion receptors

Question 3

Define pharmacodynamics.

Answer 3

The effects that a drug has on the body.

Question 4

Define an agonist.

Answer 4

Agonists are the molecules that, upon binding to their targets, causes a change in activity of those targets.

Question 5

Outline the different types of agonists.

Answer 5

1. Full agonists: bind to and activate their targets to the maximal extent possible, e.g. acetylcholine binds the nicotinic acetylcholine receptor-associated ion channel from a non-conducting to a fully conducting state.
2. Partial agonists: produce a submaximal response upon binding to their targets.
3. Inverse agonists: cause constitutively active targets to become inactive.

Question 6

Define an antagonist.

Answer 6

Antagonists inhibit the ability of their targets to be activated (or inactivated) by physiologic or pharmacologic agents.

Question 7

Outline the different types of antagonists.

Answer 7

1. Competitive antagonists: drugs that directly block the binding site of a physiologic agonist.
2. Non-competitive antagonists: drugs that bind to other sites on the target molecule, and thereby prevent the conformational change required for receptor activation (or inactivation).

Question 8

What are two important classes of drugs that act by altering conductance of ion channels? What channels to they alter?

Answer 8

1. Local anaesthetics block the conductance of sodium ions through voltage-gated sodium channels in neurons that transmit pain information from the periphery to the CNS, thereby preventing action potential propagation and, hence pain perception (nociception).
2. Benzodiazepines also act on the nervous system, but by a different mechanism. These drugs inhibit neurotransmission in the CNS by potentiating the ability of the neurotransmitter gamma-aminobutyric acid (GABA) to increase the conductance of chloride ions across neuronal membranes, thereby driving the membrane potential further away from its threshold for activation.

Question 9

Outline transmembrane G protein-coupled receptors.

Answer 9

These are the most abundant class of receptors in the human body. They are exposed on the extracellular surface of the plasma membrane, and possess intracellular regions that activate G proteins (signalling molecules that bind GTP and GDP). Examples of processes using these receptors include vision, olfaction, and neurotransmission. Stimulation of a G protein-coupled receptor causes its cytoplasmic domain to bind and activate a nearby G protein, whereupon the alpha subunit of the G protein exchanges GDP for GTP. The alpha-GTP subunit then dissociates from the beta-gamma subunit, and the alpha or beta-gamma subunit diffuses along the inner leaflet of the plasma membrane to interact with a number of different effectors.

Question 10

What are some effectors of G protein-coupled transmembrane receptors?

Answer 10

• Adenylyl cyclase: catalyses production of the second messenger cAMP.
• Phospholipase C: plays a key role in regulating the concentration of intracellular calcium. Upon activation, it cleaves PIP2, DAG, and IP3.

Question 11

Name an important class of G protein-coupled receptors.

Answer 11

Beta-andrenergic group, of which beta1 receptors control heart rate, beta2 receptors are involved in relaxation of smooth muscle, and beta3 receptors play a role in mobilisation of energy by fat cells.

Each of these receptors is stimulated by the binding of endogenous catecholamines, such as epinephrine and norepinephrine, to the extracellular domains of the receptor.

Question 12

Name an example of a drug that targets an intracellular enzyme/transduction molecule.

Answer 12

Imatinib is a selective therapy for chronic myeloid leukaemia (CML) because its selectivity targets the BCR-Abl protein, neutralising its ability to phosphorylate substrates. Imatinib was the first example of a drug targeted selectively to tyrosine kinases, and it’s success lead to the development of a number of drugs that act by similar mechanisms (dasatinib, nilotinib used in CML treatment of Imatinib-resistant patients).