L2- The concept of agonism

Question 1

explain how conventional agonists change cellular activity

Answer 1

Agonist binding induces a favourable conformational change in the binding site that is transmitted through to other regions of the receptor (activation)

The activated receptor binds to & stimulates downstream signalling pathways, to induce a change in cellular activity

Question 2

define the term efficacy

Answer 2

the a measure of an agonists ability to activate a receptor, once bound

Question 3

what is the relationship between full and patrial agonists and antagonists

Answer 3

Full agonist: high efficacy
- high receptor response
- large cellular effect
Partial agonist: lower efficacy
- less receptor response
Antagonists bind to receptors but cannot activate them so they have, no efficacy

Question 4

define the agonist-induced effect

Answer 4

The agonist-induced effect is the capacity of a bound agonist to produce an activity change within the cell

Question 5

what is f

Answer 5

efficiency of coupling
- this measures the strength of downstream signalling pathways

Question 6

what is RT

Answer 6

Receptor density
- this measures the number of receptors at the cell surface

Question 7

define the relationship between the agonist-induced effect and f, [A], efficacy, KA and RT

Answer 7

The greater these factors the stronger the agonist-induced effect

Question 8

define the term agonist potency

Answer 8

describes the relationship between dose & effect

Question 9

how is agonist potency measured

Answer 9

EC50 which is the dose at which the drug produces 50% of its maximum response

Question 10

what is the relationship between potency and EC50

Answer 10

Inverse
- the lower the EC50 the higher the potency

Question 11

describe the concept of biased agonism

Answer 11

Different agonists can activate the same receptor to cause the activation of differing signalling pathways (preferential)

Question 12

What are the potential benefits of biased agonism

Answer 12

Biased agonism will enable the separation of therapeutic and
adverse effects of a single molecule acting through a single receptor

Question 13

Give a drug example of the benefits of biased agonism

Answer 13

TRV130 (Oliceridine)
- This is an analgesic drug that preferentially activates G-protein pathways to manage pain
- Traditional analgesics such as morphine activate G-protein and Beta-arrestin pathways leading to unwanted adverse effects like respiratory depression

Question 14

System and receptor bias

Answer 14

Receptor bias – modification of a
receptor (e.g. through mutations, differential splicing, PTMs), which alters its interaction with ligands and/or effectors.

System bias – differential expression of effector elements biases specific signalling outputs over others. e.g. f