Drug-Receptor Interaction II

Agonists – Antagonists
An agonist has affinity (binding avidity)
for its receptor and alters the receptor
protein in such a manner as to generate
a stimulus that elicits a change in cell
function: “intrinsic activity“. The biological
effect of the agonist, i.e., the
change in cell function, depends on the
efficiency of signal transduction steps
initiated by the activated receptor.
Some agonists attain a maximal
effect even when they occupy only a
small fraction of receptors
. Other ligands , possessing
equal affinity for the receptor but lower
activating capacity (lower intrinsic activity),
are unable to produce a full maximal
response even when all receptors
are occupied: lower efficacy. Ligand B is
a partial agonist. The potency of an agonist
can be expressed in terms of the
concentration (EC50) at which the effect
reaches one-half of its respective maximum.
Antagonists attenuate the effect
of agonists, that is, their action is
“anti-agonistic”.
Competitive antagonists possess
affinity for receptors, but binding to the
receptor does not lead to a change in
cell function (zero intrinsic activity).
When an agonist and a competitive
antagonist are present simultaneously,
affinity and concentration of the two rivals
will determine the relative amount
of each that is bound. Thus, although the
antagonist is present, increasing the
concentration of the agonist can restore
the full effect . However, in the presence
of the antagonist, the concentration-
response curve of the agonist is
shifted to higher concentrations (“rightward
shift”).
Molecular Models of Agonist/Antagonist
Action
Agonist induces active conformation.
The agonist binds to the inactive receptor
and thereby causes a change from
the resting conformation to the active
state. The antagonist binds to the inactive
receptor without causing a conformational
change.