L6 - Quantitative receptor pharmacology

Question 1

describe the impact of competitive receptor antagonists on fractional receptor occupancy and agonist-induced effects.

Answer 1

Competitive antagonists cause a rightward shift in receptor occupancy but do not impact agonist effects.

Equal agonist-induced effects (e.g. 50% Emax) in the absence and presence of the antagonist are due to equal receptor occupancies by the agonist.

Question 2

describe the Schild analysis

Answer 2

Schild analysis determines which receptors are mediating agonist-induced responses, via the use of receptor-selective, competitive antagonists

Question 3

what is the Schild equation

Answer 3

log (Dose Ratio-1) = log [B] - log [kB)

Question 4

what is a pA2 value

Answer 4

It is the value on a Schild plot what the line intersects with the X-axis
p: -log
A: antagonist
2: 2-fold shift

Question 5

explain the relationship between pA2
value & antagonist affinity

Answer 5

pA2 is the value used to measure antagonist affinity for a receptor, the higher the pA2 value the higher the affinity for the receptor

Question 6

interpret Schild plots (using modified SPIKES mnemonic

Answer 6

S- LINEAR
P - provides the pA2 value
I - slope – should not be significantly different from 1.0. If slope < 1, -logKB is over-estimated & if slope > 1, then -logKB is under-estimated.
K - is a measure of the affinity of antagonist for receptor mediating the response
E - compare observed KB value to known KB values to eliminate receptor subtypes
S - Using many selective antagonists, use process of elimination

Question 7

slope >1.0, non-linear

Answer 7

The antagonist is toxic at high []
- change antagonist

Question 8

slope >1.0 for all [antagonist]

Answer 8

The antagonist binds (pseudo)irreversibly to the receptor
- No remedy: Schild plots are only suitable for competitive antagonists

Question 9

slope >1.0 if antagonist is a
substrate, (but slope <1.0 if
the agonist is a substrate)

Answer 9

A saturable uptake process
exists (agonist or antagonist)
- Block saturable uptake process e.g. cocaine to block uptake of noradrenaline

Question 10

slope <1.0, non-linear esp. at high [antagonist]

Answer 10

The antagonist binds allosterically to the receptor
- No remedy: Schild plots are only suitable for competitive antagonists