Lecture 17

Question 1

Receptor

Answer 1

• Specific macromolecule that is the target for drug binding, initial site of action.
• Most are proteins, regulatory functions
• Can also be cell membranes, DNA, RNA, etc.
• Pharmacologically, drug-target interactions must elicit a biological response
• *NOT ALL DRUG BINDING PROTEINS ARE RECEPTORS**

Question 2

PK v.s. PD

Answer 2

PK ==> Body’s action on drug (ADMET

PD ==> Drug’s action on body (drug interactions/binding)

Question 3

Ligand

Answer 3

Moiety that interacts with receptor

Question 4

Agonist

Answer 4

Stimulates receptor action. Can also be partial agonists.

Question 5

Antagonist

Answer 5

Blocking receptor action, can occur by multiple mechanisms. Can also be partial antagonists.

Question 6

Receptor Theory (4)

Answer 6

1. Receptors must possess structural and steric specificity.
2. Receptors are saturable and finite (limited binding sites).
3. Receptors must possess high affinity for endogenous ligand at physiological concentrations.
4. Once ligand binds to receptor, a recognizable event needs to occur.

Question 7

Drug Requirements

Answer 7

• Must have right size, charge, shape, and atomic composition to interact
• Drugs vary in chemical properties
• Shape must permit binding to receptor
• Chirality can dictate receptor interactions

Question 8

Saturable + Finite

Answer 8

• Relationship between drug concentration , effect, and receptor binding
• Drug concentration at which the receptor occupancy is at 1/2 maximal is denoted as EC50 for biological activity of that drug

Question 9

High Affinity

Answer 9

• Receptor occupancy theory assumes that the response is proportional to the number of occupied receptors
• Receptor occupancy is a function of available ligand and affinity

Question 10

Kd

Answer 10

-Measure of the reversible interaction between drug and receptor (denotes affinity)

Forward Reaction: [D][R]k+1
Backwards Reaction: [DR]k-1
Equilibrium: [D][R]k+1 = [DR]k-1

Kd = [D][R]/[DR] = k-1/k+1

Question 11

Receptor Occupancy + Kd

Answer 11

1. As the agonist concentration increases, receptor occupancy increases.
2. Small Kd = high affinity, typically very small number (uM, nM, pM)
3. As agonist affinity increases, receptor occupancy increases

Question 12

Receptor Occupancy + Drug Response

Answer 12

• When [D] = Kd, drug occupancy will occupy ~50% of receptors
• In most cases, 50% occupancy = Kd
• Graphed as Occupancy of Receptors v.s. log[drug]

EXCEPT…

• Sometimes full effect is achieved with less than full receptor occupancy
• EC50 (Effective Concentration at 50%) is the effective concentration producing 50% response
• In this case, if fully occupied, will approximate Kd
• Graphed as Response v.s. log[drug]

Question 13

Spare Receptors

Answer 13

• Maximal response with less than 100% occupancy

- More likely in signaling cascade due to a component of the cascade being limiting

Question 14

Potency

Answer 14

• Property that can be also determined from dose-response curves
• Potency - dose of a drug required to produce an effect relative to a given or implied standard of reference
• More potent requires less drug to elicit the same response as a less potent drug (lower Kd or EC50 = less potent)
• *Most useful drugs are not necessarily the most potent**

Question 15

Potency Comparisons

Answer 15

• Can get ratios of potency that can be graphed on response v.s. log(dose) graphs
• Drugs being compared have the same mechanisms

Question 16

Efficacy

Answer 16

• Measure of maximal effect induced by interaction of drug with its specific receptors
• Exerting maximal biological response from a cell (regardless of potency) = agonist
• Drug that exerts less than maximal biological response from cell = partial agonist

Question 17

Partial Agonists

Answer 17

-Can have same affinity as full agonist, does NOT elicit maximal response
-Competitively inhibit response of full agonist
-Many drugs used as “antagonists” are actually partial agonists
-Can be useful so that you aren’t completely blocking a particular response
EX: Buprenorphine, safe analgesic than morphine that decreases the risk of respiratory depression

Question 18

Receptor-Effector Coupling

Answer 18

• Agonist binding first step
• Effector coupling links initial receptor event to downstream cascade including additional proteins
• Partial agonists may not fully activate a receptor or promote full coupling to signaling cascade

Question 19

Allosteric Agonists

Answer 19

-Binds to a different site other than the action site
-Does not activate receptor but increases its binding affinity to endogenous ligand
EX: Benzodiazepines

Question 20

Summary of Receptor Binding

Answer 20

• Magnitude of drug effect is proportional to the number of receptors occupied by drug molecules.
• Binding is proportional to the concentration of the drug and the concentration of receptors.
• The concentration of the ligand (drug) and the amount of receptors are key variables governing the responses to drugs.

Question 21

Kd Summary

Answer 21

• Although KD gives a measure of potency is not the best measure for comparison because 50% receptor occupancy may not equal 50% effect.
• This is due to spare receptors in which most tissues have more receptors than are needed to get a full effect.
• Therefore dose-response curves measure effect (EC50 values) are used to determine amount of drug to produce a given effect.