Chapter 8: Receptors as Drug Targets

Question 1

What is induced fit?

Answer 1

ligand bind and induces structural changes to binding site

Question 2

What do receptors do?

Answer 2

bind an extracellular ligand and transmit a cellular signal inside the cell

Question 3

Agonist

Answer 3

a drug that binds to a receptor and activate, mimicking the effect of a natural messenger/ligand
- Eq: bind and favor active conformation

Question 4

Antagonist

Answer 4

a drug that binds to a receptor and blocks activation (doesn’t activate it)
- doesn’t inhibits but blocks native ligand from binding
-no effect on equilibrium: bind and show no preference for active vs inactive conformation

Question 5

Partial agonist

Answer 5

has an intermediate effect, between an antagonist and a pure agonist

Question 6

Inverse agonist

Answer 6

a drug that binds to a receptor, blocks native ligand binding, and inhibits any constitutive activity
- eq: bind and favor inactive conformation

Question 7

What must we consider when designing an effective agonist?

Answer 7

• the correct binding groups are present compared to the native ligand
• the binding groups are in the correct location
• the drug must be the correct size

Question 8

What does drug structure include?

Answer 8

includes the important binding groups and a scaffold

Question 9

Drug Scaffold

Answer 9

• holds the functional groups in place
• can vary in structure/ composition
• steric clashes could prevent an agonist from binding

Question 10

Allosteric Modulators

Answer 10

• an agonist may target an allosteric binding site
• mimic the effect of a positive allosteric effector (increasing receptor activity)

Question 11

What are some general antagonist strategies?

Answer 11

• bind to the active site but not induce a conformational change (no induced fit)
• bind to the active site and distort the shape to a non-native conformation
• utilize other binding regions in the active site not used for ligand binding

Question 12

Constitutive Activity

Answer 12

inherent/underlying activity in the absence of ligand
- (helpful to think about receptors as being in equilibrium between active/inactive states)

Question 13

Desensitization

Answer 13

• treatment with an agonist can lead to desensitization- making the drug an antagonist

Question 14

Although the mechanism for desensitization is unclear, what are some reasons it may happen?

Answer 14

• receptor may be modified by failsafe mechanisms (ex: phosphorylated)
• receptor may be transported into the cell via endocytosis and then recycled or degraded
• less receptor means more drug is needed for desired effect

Question 15

Sensitization

Answer 15

treatment with an antagonist can lead to sensitization
- cell may try to overcome the inhibited receptor by expressing more receptor
- hypersensitive to available ligand
- more receptors can lead to tolerance and dependence on the drug
- upon cessation, symptoms of withdrawal are present until the normal receptor levels are reestablished

Question 16

Affinity

Answer 16

measures binding

Question 17

Efficacy

Answer 17

maximum biological effect of the drug

Question 18

Potency

Answer 18

the amount of drug required to achieve a defined biological effect
- small dose=more potent

Question 19

What are some reasons why we wouldn’t want to use the native ligand of a receptor as the drug?

Answer 19

• metabolism
• route of administration
• better specify for target
• stability
• tighter/higher binding affinity