Agonism and antagonism

Question 1

Describe trends in GPCRs in trends in indications

Answer 1

Most treat pain, hypertension or allergy
CNS disorders strong category - Alzheimer’s and obesity

Question 2

Describe trends in classes of target

Answer 2

Notable growth in ligands and serine/threonine kinases
Few new targets for ligand-gated ion channels
many still unexplored

Question 3

Describe GPCR key statistics

Answer 3

66 GPCR drugs have reached clinical trial but not yet approved
224 yet to be targeted in clinical trials

Question 4

Describe trends in molecule type

Answer 4

Mostly small molecules (86%)

Question 5

Describe drug mode of action

Answer 5

Antagonism and agonism still common but others emerging

Question 6

What are Orthosteric binding sites

Answer 6

Endogenous ligand in usual binding site

Question 7

What are Allosteric binding sites

Answer 7

Allosteric ligand bound somewhere not the usual binding site

Question 8

What is an allosteric modulator

Answer 8

Drugs that bind allosterically - change the response to the orthosteric ligand

Question 9

Describe allosteric modulators (PAMs)

Answer 9

Increase affinity/efficacy/potency of orthosteric ligand

Question 10

Describe negative allosteric modulators (NAMs)

Answer 10

Decrease affinity/efficacy/potency of orthosteric ligans

Question 11

Describe allosteric agonist/inverse agonist

Answer 11

Bind allosterically and directly activate/inactivate receptor

Question 12

2 examples of allosteric modulator drugs

Answer 12

Cinacalcet - PAM of calcium sensing receptor for hyperparathyroidism
Maraviroc - NAM of chemokine receptor (CCR5) for prevention of cellular entry of HIV

Question 13

Why are receptor ‘subtypes’ important

Answer 13

Have different functions but share the same endogenous ligand and similar orthosteric binding site

Question 14

Why are allosteric drugs useful

Answer 14

Receptor ‘subtypes’ make it difficult to make selective drugs based on orthosteric binding site
Allosteric is likely also more diverse