Receptor Theory 2

Question 1

What does the occupancy equation predict from a full agonist?

Answer 1

that the concentration required to produce 80% of the max response will be 16x greater than the concentration required to produce 20% of the max response

Question 2

How does Stephensons model allow for two drugs to act as full agonists without having the same efficacy?

Answer 2

Based on the idea that 10 arbitrary units is a max response…different potencies and efficacies can result in a max response
i.e. f= 50% and efficacy = 20 200.5 = 10
f=10% and efficacy = 100 0.1100 = 10

Question 3

Prove that the minimum efficacy for a full agonist would be 10

Answer 3

agonist would require to occupy the whole receptor population as 10*1.0 = 10

Question 4

Why are EC50 and Kd concentrations not identical when spare receptors are involved?

Answer 4

Kd is the agonist concentration where 50% of the total receptor population is occupied
If an agonist only requires 10% on the population to elicit 50% of the maximal response then Kd and EC50 will be different

Question 5

What is the equation representing the agonist fractional occupancy in the presence of a reversible competitive antagonist?

Answer 5

E/Emax = [D]/[D]+Kd(1+[a]/Kant)

Question 6

What type of graph is shown with a reversible competitive antagonist?

Answer 6

rectangular hyperbola shifted to the right

Question 7

How does the presence of a reversible competitive antagonist represent on a double reciprocal plot?

Answer 7

no change in y-axis but new x-axis intercept

Question 8

How can the dose ratio be used in a Schild plot to determine Kant?

Answer 8

D2/D1, D3/D1, D4/D1 plotted will show a straight line slope of 1 and the x-axis intercept gives log Kant

Question 9

What is the pA2 value?

Answer 9

a numerically simplified way of indicating the antagonist dissociation constant

Question 10

Give an example of a reversible non-competitive antagonist

Answer 10

Ketamine non-competively inhibits NMDA glutamate receptor

Question 11

Give an example of an indirect antagonist

Answer 11

Nifedipine blocks VGCC that noradrenaline activates through a-adrenoceptors

Question 12

How is the agonist fractional occupancy in the presence of a non-competitive antagonist represented?

Answer 12

E/Emax = [D]/([D]+Kd)(1+[A]/Kant)

Question 13

What is the effect of the non-competitive antagonist on a concentration response curve?

Answer 13

same Kd but different Emax

Question 14

What is the effect of the non-competitive antagonist on a double reciprocal plot?

Answer 14

change in y-intercept but not x-intercept

Question 15

What are the two possible scenarios for allosteric effects producing non-competitive antagonism?

Answer 15

antagonist has no effect on agonist binding but changes receptor conformation to prevent agonist from activating response
conformational change decreases strength of agonist binding or prevents binding

Question 16

Given an example of a non-competitive allosteric antagonist acting on mAChRs

Answer 16

Gallamine

Question 17

Give an example of an allosteric antagonist that regulates enzyme action

Answer 17

d-tubocurarine inhibits acetylcholinesterase metabolism of ACh

Question 18

Give an example of an irreversible competitive antagonism

Answer 18

Naloxone for mu-opioid receptor antagonists as forms a covalent bond

Question 19

What is the effect of irreversible competitive antagonism on Emax and Kd?

Answer 19

Emax is reduced

Kd is the same as agonist binds free receptors

Question 20

What is an inverse agonist?

Answer 20

an agent that binds to the same receptor as an agonist but induces a pharmacological response opposite to that agonist

Question 21

What is cooperativity?

Answer 21

displayed by some receptors and enzymes that have multiple binding sites where the affinity for a ligand is increased or decreased upon the binding of a ligand to a site

Question 22

What is homotropic cooperativity?

Answer 22

when the molecule causing the cooperativity is the one that will be affected

Question 23

what is heterotropic cooperativity?

Answer 23

where a third substance causes the change in affinity - allosteric cooperativity

Question 24

How is the general relationship for co-operativity shown?

Answer 24

E= Emax[D]^n/[D]^n +Kd

Question 25

What kind of graphs are produced by positive and negative cooperativity?

Answer 25

n>1 for positive creates sigmoidal

n

Question 26

What is the equation for cooperativity also known as?

Answer 26

the Hill Equation

Question 27

How can the equation be changed around to represent the equation of a straight line?

Answer 27

log10(E/Emax-E) = nlog10[D] - log10 Kd

Question 28

Why is it useful that hill plots can give values for n that are not whole numbers?

Answer 28

indicates strongly whether there is cooperativity or multiple receptor populations as receptors can’t bind a fraction of a drug

Question 29

What is an advantage of using an allosteric modulator as a therapeutic target?

Answer 29

they have not undergone the same evolutionary stresses to accommodate an endogenous ligand so offer greater GPCR selectivity

Question 30

Why do allosteric modulators have less potential for toxic effects?

Answer 30

they have a ceiling level of effects irrespective at the administered dose

Question 31

What is an advantage of allosteric modulators not expressing appreciable efficacy?

Answer 31

it has the ability to selectively tune up or down tissue responses only when the endogenous agonist is present