W2.3_Agonist and Antagonist

Question 1

Explain how drug binding to a receptor can induce a biological response. State the nature of response.

Answer 1

• Drug binds to unoccupied receptor -> activate receptor -> signal transduction -> biological response
• Interacts with/binds to cell membrane/in the cell
• Target forms tight bonds with drug
• High specificity of drug (size/shape/stereospecificity)
• Forms target-drug complex and produces response
• Nature of response: depends on type of target, what the target is linked to

Question 2

State the purposes of functional groups in drug molecules (2) and its relationship to drug-target interaction. Rank the three related chemical bonding forces from weakest to strongest. Can drugs with different structures bind to the same receptor? What is the purpose of studying the chemical structure of drug molecules?

Answer 2

• Functional groups of drugs gives drugs their properties (how it interacts with target, mechanism of action that affects administration/metabolism/side/adverse effects)
• Determines 3D shape
• Drug-target interaction: depends on functional groups and charge distribution (≈ lock and key)
  –> van der Waals’ forces (weakest)
  –> Dipoles (uneven distribution of electrons between atoms in molecules)
  –> Ions (strongest bonds, in weak acids/bases)
• Similar drug structures can bind to same receptor, but have different affinity/efficacy due to differences
• Important in learning drug mechanism, effects, side effects, and potential interactions

Question 3

Contrast orthostric and allosteric binding. Contrast afffinity and efficacy, and define rate of dissociation.

Answer 3

• Orthosteric binding (to main active binding site) vs Allosteric binding (to alternative binding site)
• Affinity: capacity to bind (degree of attraction)
• Intrinsic Efficacy: capacity to excite receptor to produce response (degree of response)
• Rate of dissociation: rate of drug coming off the receptor

Question 4

State the different wordings used for drug molecules that can initiate a positive/negative effect in proteins.

Answer 4

Receptor: agonist/antagonist
Enzyme & Transporter: activator/inhibitor
Ion channel: opener/blocker

Question 5

What is the effect of agonists? What are the four types of agonists? Explain the effects of allosteric modulators.

Answer 5

• Activate (have affinity and efficacy), all bind to same active site (orthosteric)
• Full agonist: full response (maximum)
• Partial agonist: never full response
• Biased agonist: activates receptor’s different signalling cascade
• Inverse agonist: produces opposite effect of natural ligand
• Allosteric modulators: bind allosterically to alter affinity/efficacy of agonist binding orthosterically
• Can be positive (PAM)/negative (NAM)/neutral (SAM)

Question 6

What is the effect of antagonists? What are the different types of antagonists?

Answer 6

• Prevent agonist binding (have affinity but no efficacy as there is no response)
• Competitive (orthosteric) vs Non-competitive (allosteric)
• Reversible (short-lived bonds, dissociate easily)/Irreversible (strong covalent bonds, X dissociate)

Question 7

Explain the conformational states of receptors by referring to the diagrams. Relate the process to constituitively active receptors and inverse agonists.

Answer 7

• R (resting state): at rest in equilibrium
• R* (active state): produce biological effect
  With agonist activation:
• LR can bind but cannot produce effect
• LR* can bind and produce effect
• Constitutively active receptors: always at R*
• Inverse agonists produce opposite effect

Question 8

Referring to a dose-response graph, what does it indicate? Explain the curve and the EC50 value.

Answer 8

• Effects of increasing dose/concentration in size of response
• Determine properties of drug
• Curve plateaus off due to limited amount of receptors
• EC50: dose needed to produce 50% of maximum response

Question 9

Referring to a potency graph, what does it indicate? Compare the importance between affinity and potency.

Answer 9

• Measure how much drug is needed to produce a certain size of effect (EC50)
• Allows comparison between drugs at same receptor
• Affinity is more important than potency

Question 10

Describe how competitive and non-competitive antagonists change the parameters in a dose-response graph. How does potency affect EC50/IC50 value?

Answer 10

• Competitive antagonist: parallel shift of curve, no change in maximum response
• Non-competitive antagonist: no change in EC50, decrease maximum response
• Increase potency reduces EC50 or IC50 (for inverse agonists)

Question 11

Define functional antagonism.

Answer 11

drugs binding to different receptors and produce opposing functional effects (contraction and relaxation of smooth muscle at the same time, not a good thing)