Cii / 25A01 / 24A01 / 22B19: What are receptors? (20% marks). Discuss the relationship between the properties of a drug and potential receptor response under the following headings: agonists, partial agonists, inverse agonists and antagonists (80% marks)
25A01: Exam Report
Define receptors and provide a brief outline of their classification. (20% of marks).
Define the following terms and outline the receptor-drug binding and activation characteristics of each:
Agonists (20% of marks).
Partial agonists (20% of marks).
(ii) Inverse agonists (20% of marks).
(iv) Antagonists (20% of marks).
33% of candidates passed this question.
The first part of the question required a definition of receptors and outline of their classification.
Good answers described receptors as proteins or glycoproteins that are found on cell membranes, on membranes of intracellular organelles or in the cytosol / nucleus and contain a region to which a natural ligand or drug binds specifically (receptor site or recognition site) to bring about a conformational change and subsequent response.
Receptors can be grouped into 3 classes depending on mechanism of action, altered ion permeability, production of intermediate messengers and regulation of gene transcription.
Further descriptions of the different types of receptors/downstream messages were not required.
The second part of the question is well covered in the outlined pharmacology textbooks namely Peck and Hill, Stoelting and Goodman and Gillman’s.
This is best answered by applying receptor theory: namely that receptors can exist in two states, an active and inactive state.
Agonists stabilise the receptor in the active state, partial agonists occupy (and block) the binding site but do not completely favour the active state, whilst inverse agonists stabilise the receptor in the inactive state.
Antagonists simply block the binding site and prevent agonists from binding.
A description then of affinity and intrinsic activity of each group would complete your answer.
24A01: Exam Report
What are receptors (20% of marks)?
Discuss the relationship between the properties of a drug and potential receptor response under the following headings (20% of marks each):
Agonists
Partial agonists
Inverse agonists
Antagonists
28% of candidates passed this question.
A good answer provided a definition of a receptor as a protein/glycoprotein that undergoes a conformational change upon ligand binding. They then gave an overview of where these are found and the mechanisms of activitation/downstream processing.
A definition of each type (agonist, antagonist, partial agonist and inverse agonist) was expected with reference to the intrinsic activity at the receptor and the affinity for the receptor.
A good answer also touched upon law of mass action (D+R=DR) and how this equilibrium is altered by each.
Concepts such as reversible and irreversible binding and its implications as well as competitve and non-competitive antagonism would elevate the answer.
22B19: Exam Report
What are receptors? (20% marks).
Discuss the relationship between the properties of a drug and potential receptor response under the following headings:
Agonists
Partial agonists
Inverse agonists and antagonists (80% marks)
31% of candidates passed this question.
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.
Cii / 25A01 / 24A01 / 22B19:
What are receptors? (20% marks).
Discuss the relationship between the properties of a drug and potential receptor response under the following headings: agonists, partial agonists, inverse agonists and antagonists (80% marks)
Receptors are protein molecules to which ligands bind in order to effect the regulation of a cellular process. In vivo, they function to recognise and respond to endogenous chemical signals.
4 Main Types of Receptors
Ligand Gated Ion Channels
GPCR
Kinase Linked
Nuclear Receptors
Structure
Ligand Gated Ion Channels
Oligomeric (often pentameric) assembly of subunits surrounding a central pore on cell membrane
GPCR
Serpentine proteins consisting of 7 transmembrane helices with intracellular G protein coupling domain
Kinase Linked
Large proteins consisting of a single membrane spanning helical region with a large extracellular ligand binding domain
Nuclear Receptors
Monometric structure with separate receptor and DNA binding domains
Effect after ligand binding
Ligand Gated Ion Channels
Opening of central pore → nerve hyperpolarisation OR depolarisation due to ionic flux
GPCR
Binding of ligand causes the receptor to activate the G protein (composed of α, β, γ subunits) which bind GDP.
Upon stimulation, GTP replaces GDP → α-GTP subunit dissociates to activate/inhibit an effector protein
Kinase Linked
Binding of ligand causes dimerisation leading to autophosphorylation of tyrosine residues on the intracellular domain → flow on signal transduction via intracellular protein kinases
Nuclear Receptors
Binding of ligand effects changes in gene transcription
Site
Ligand Gated Ion Channels
Membrane of nerves / muscles
GPCR
Cell membrane
Kinase Linked
Cell membrane
Nuclear Receptors
Intracellular
Example
Ligand Gated Ion Channels
Nicotinic ACh receptors, GABA-A, NMDA and AMPA receptors
GPCR
Muscarinic ACh receptors, adrenoreceptors
Kinase Linked
JAK kinases
Nuclear Receptors
Steroid hormone receptors
Agonists
Agonists are drugs that bind to physiological receptors to elicit the same response as the endogenous ligand
- A full agonist which drug which produces a maximal response at the receptor site. i.e. high affinity and an intrinsic activity of 1
- Affinity is how avidly a drug binds to its receptor. Described by the association constant, Ka
- Intrinsic activity (IA) is the ability of a bound agonist to cause a maximum response. Maximum IA is 1
- g. morphine at opioid receptors
Partial Agonist
A partial agonist is a drug which is unable to induce maximal activation of a receptor population, regardless of the amount of drug applied
- High affinity but intrinsic activity between 0 and 1
- g. buprenorphine at opioid receptors
Inverse Agonist
An inverse agonist is a drug that binds to the same receptor as an agonist but induces a pharmacological response opposite to that of the agonist
- This is due to the agonist being relatively more selective for the resting state of the receptor
High affinity but intrinsic activity between -1 and 0
Author: Andrew Wang