L3: Measuring agonist and antagonist activity part 2 (there is more)

Question 1

agonist (A) binding?

Answer 1

XA + (Ntot-NA) (forward reverse arrows) NA
The n things: gives you number of receptors not bound
NA: Number of receptors bound by agonist

at equillibirum number of drug molecules binding is equal and opposite to those unbinding

XA= agonist concentration

Question 2

Hill-Langmuir equation

Question 3

what us an agonist

Answer 3

an agonist binds to a receptor and also elicits a response
A+R reverisble arrows
(affinity)
to AR reverisble arrows
receptor activation
(efficacy)
to AR*
This response can be opening of an ion channel, activation of a G-protein
or activation of an enzyme depending on the receptor type

An agonist is a drug with affinity (KA) and efficacy both of which can be quantified

full agonist: A full agonist has high efficacy i.e. produces a maximal effect before all available receptors are occupied

Question 4

NEED TO KNOW CONC AND LOG CONC RESPONSE CURVES

Question 5

ec50

Answer 5

Effective concentration which produces 50% of the maximal effect
A functional measure
A product of both affinity and efficacy

IC50 – Concentration to produce 50% inhibition

LD50 - Dose to produce death in 50% of the subjects

Question 6

PARTIAL agonists

Answer 6

Has affinity for the receptor but low efficacy
It will not produce a maximum response

has low efficacy i.e. occupies all of the available receptors without producing a maximal response

Question 7

inverse agonists

Answer 7

A recent concept
In the past most experiments assumed basal activity of a receptor was zero
A+R—-> AR—-> AR*
an agonists increases the probability of receptor activation
but
R—-> R*
in absence of agonist, receptor activation is not 0
There is some evidence for this constitutive activity indeed some diseases
are cause by mutant receptors that a highly constitutively active

Then some drugs might reduce the number of activated receptors at rest
These are termed inverse agonists

An inverse agonist reduces constitutive receptor activation

Question 8

pharmacology, homeopathy and herbal medicine

Answer 8

Homeopathy: giving patients medicines that contain no medicine whatsoever
Herbal medicine: giving patients an unknown dose of an ill-defined drug, of unknown effectiveness and unknown safety
Pharmacology is based on physiochemical constants that describe the binding of drugs to receptors

Question 9

competitive reversible antagonists

Answer 9

Has affinity but zero efficacy
It binds to the receptor but induces no response
However it binds in such a way to prevent agonist binding (competes)

Question 10

PA2 and KB

Answer 10

pA2 is the negative log10 of the concentration of antagonist required to shift the agonist concentration response curve 2-fold to the right
pA2 = 50% of the receptors occupied by antagonist therefore pA2 = KB
This means we do not have to do binding experiments to measure the equivalent of the KB
So if pA2 = 9.0 then 1 x 10-9 M (1 nM)
It is independent of the agonist used
why kb (PA2) is better at defining receptor affinity than KA:
Can compare binding data (KB) with functional data (pA2)
Competitive antagonist have zero efficacy
KA can change when receptor is bound by its effector
Uncoupled receptor has high affinity for agonist
A receptor when coupled to a G-protein has lower affinity for agonist
The same receptor coupled to different G-proteins may have different KAs for the same agonist