receptors. It primarily relates to G-protein-coupled receptors that can bind to two
or more G-proteins.- Potency: This is a measure of the concentration of agonist required to produce the
maximum effect; the more potent the agonist the smaller the concentration required.
The potency of an agonist is related to the position of the sigmoidal curve on the log
dose axis. It is expressed in a variety of forms including theeffective doseor
concentration for 50% maximal response,ED 50 or EC 50. On a semi-logarithm plot,
the value emerges as pED 50 or pEC 50 value (i.e.log 10 ED 50 ). Thus an agonist with
EC 50 of 3 10 ^5 M would have a pEC 50 of 4.8. The potency of a reversible antagonist
is expressed by its pA 2 value, defined as negative logarithm of the concentration of
antagonist that will produce a two-fold shift in the concentration–response curve for
an agonist. - Affinity: This is a measure of the concentration of agonist required to produce 50%
binding. As will be shown in the following section, affinity is a reflection of both the
rate of association of the ligand with the receptors and the rate of dissociation of the
resulting complexes. The rate of association is a reflection of the three-dimensional
interaction between the two and the rate of dissociation a reflection of the strength of
binding within the complexes. Affinity of an agonist can be expressed by anaffinity
orbinding constant,Ka,but is more commonly expressed as adissociation constant,
Kd, of the receptor–ligand complex whereKdis equal to the reciprocal ofKa. The
affinity of receptors for an antagonist is expressed by the corresponding dissociation
constantKb. - Selectivity: This is a measure of the ability of an agonist to discriminate between
receptor subtypes. This is particularly important from a therapeutic perspective. - Functional selectivity: This is a measure of the ability of the agonist to induce
selective response from receptors capable of promoting more than one transduction
activity.
17.2.2 Constitutive receptor activity, inverse agonists and receptor activation
The long-held view of receptor–agonist interaction was based on atwo-state model
that visualised that the binding of the agonist (A) by the receptor to form a receptor–
agonist complex triggers a conformational change in the receptor that converts it
from adormantorresting inactive state(R) to anactive state(R*):RþA! AR! AR! transduction via
inactive inactive active effectorThe formation of the active state of the receptor initiates a transduction (linking)
process in which the receptor activates aneffector protein. The effector protein
may be the receptor itself or a distinct protein that is either attached to the inside of
the membrane or free in the cytoplasm. This activated effector either allows the
passage of selected ions across the membrane thereby changing the membrane
potential or it produces asecond messengerwhich initiates acascadeof molecular
events, involving molecules located on and/or at the internal surface of the cell667 17.2 Quantitative aspects of receptor–ligand binding