Question 19

College Answer

The description of a receptor was worth 20% thus it was expected that detailed information on the different forms of receptors, their structure, the resultant conformational change when activated and where they are found would be provided for full marks. Most candidates were able to correctly define an agonist, antagonist, partial agonist and inverse agonist. Unfortunately, this was the limit of most answers.
Candidates were expected to provide details of drug or agonist/receptor interaction discussing the terms affinity/intrinsic activity and how different mechanisms of binding and interacting with the receptor alters these terms.

Discussion

To be clear, that "detailed information on the different forms of receptors, their structure, the resultant conformational change when activated and where they are found" was attributed 20% of the marks, which means it would have needed to be written in two minutes, and given that even the fastest hand writers in the world can produce only about 28 words per minute, the maximum word count for this section would have been 56 words. So, receptors, in a soundbite:

• Receptors are macromolecules involved in chemical signalling (eg. enzymes, ion channels, transmemebrane kinases, cytokines, G-protein-coupled receptors)
• Drugs interact with receptors to change their state
• This translates into physiological effect and determines the quantitative relationship between dose and effect.
• Competition of mutually exclusive molecules for the same receptors explains agonist, partial agonist and antagonist drug activity

(that's 55 words in total)

For the rest of the 80% of the mark, "the relationship between the properties of a drug and potential receptor response" sounds a lot like a list of definitions, as the examiners gave us headings to that effect, and many would have probably left it at that (which is why "this was the limit of most answers"). But then, we see in the college comments that the stem does not contain all of the examiner's expectations.  A discussion of "the terms affinity/intrinsic activity and how different mechanisms of binding and interacting with the receptor alters these terms" was also necessary for a full mark.

Agonists

• An agonist is a ligand that binds to a receptor and alters the receptor state resulting in a biological response
• A full agonist reaches the maximal response capability of the system
• Intrinsic activity refers to the maximal possible effect that can be produced by a drug (as compared to a reference full agonist)
• Affinity in chemistry is the tendency of dissimilar chemical species to form chemical compounds, and is described by the dissociation constant (K_d ), which is the rate constant of dissociation at equilibrium, defined as the ratio k_off / k_on, where:
  • k_off  is the rate constant of dissociation of the drug from the receptor
  • k_on is the rate constant of association of the drug to the receptor

Partial agonists

• A partial agonist does not reach the maximal response capability of the system even at full receptor occupancy, i.e. it has lower intrinsic activity than a full agonist, even where it has similar affinity for the receptor
• A partial agonist acts as an antagonist in the presence of a full agonist (if they compete for the same receptors)

Inverse agonists

• An inverse agonist is a ligand that, by binding to receptors, reduces the fraction of them in an active conformation. 

Antagonists

• An antagonist is a drug that reduces the action of another drug or endogenous receptor ligand
• A competitive antagonist competes for the same binding site with an agonist, and their binding is mutually exclusive
• A non-competitive antagonist can prevent the action of an agonist without any effect on the binding of the agonist to the receptor.
• An insurmountable antagonist can reduce the intrinsic activity of the agonist, and this inhibitory effect is not affected by increasing agonist concentration.

Pleuvry, Barbara J. "Receptors, agonists and antagonists." Anaesthesia & Intensive Care Medicine 5.10 (2004): 350-352.

Wyllie, D. J. A., and P. E. Chen. "Taking the time to study competitive antagonism." British journal of pharmacology150.5 (2007): 541-551.

Neubig, Richard R., et al. "International Union of Pharmacology Committee on Receptor Nomenclature and Drug Classification. XXXVIII. Update on terms and symbols in quantitative pharmacology." Pharmacological Reviews 55.4 (2003): 597-606.

Kenakin, T. Pharmacologic analysis of drug±receptor interaction 3rd ed. New York: Raven Press, 1997.

Eddy, M. D. "Elements, principles and the narrative of affinity." Foundations of Chemistry 6.2 (2004): 161-175.