P1: PCX Printer: Yet To Come
9780521704632c03 CUFX213A/Peck 9780521618168 December 27, 2007 13:30
3 Drug actionmaximum possible response can never be achieved. This is the situation with partial
agonists. Therefore:
An agonist has significant receptor affinityandfull intrinsic activity (IA=1).
An antagonist has significant receptor affinity but no intrinsic activity (IA=0).
A partial agonist has significant receptor affinity but only fractional intrinsic activity
(0 < IA <1).
An inverse agonist can be full or partial with− 1 ≤IA<0.Receptor agonism
Full agonists
Full agonists are drugs able to generate a maximal response from a receptor. Not
only do they have a high affinity for the receptor, but also they have a high intrinsic
activity. In clinical terms, the potency of the drug is determined by its KD; the lower
the KDthe higher the potency. For many drugs, the ED 50 (the dose producing 50% of
the maximum response) corresponds to the KD.Partial agonists
If an agonist drug has an intrinsic activity less than 1, such that it occupies receptors,
but produces a submaximal effect compared with the full agonist, it is termed a partial
agonist. The distinguishing feature of partial agonists is that they fail to achieve a
maximal effect even in very high dose (i.e. with full receptor occupancy) (Figure
3.3(c)C). An example of a partial agonist is buprenorphine acting at theμ-opioid
receptor. Partial agonists may act as either agonists or antagonists depending on
circumstances. If used alone, they are agonists. When combined with a full agonist
they produce additive effects at low doses of the full agonist, but this switches to
competitive antagonism as the dose of full agonist increases; the full agonist needs
to displace the partial agonist in order to restore maximum effect. In the case of partial
agonists the equilibrium between active and inactive forms can never be entirely in
favour of the active conformation, so the link between activation of receptor and
effect is only a fraction of that seen with full agonists.Inverse agonists
It is possible for a drug to bind and exert an effect opposite to that of the endogenous
agonist. Such a drug is termed an inverse agonist and may have high or moderate
affinity. The mechanism of inverse agonism is related to a constitutive action of
receptors; some receptors can show a low level of activity even in the absence of a
ligand, since the probability of taking up an active conformation is small but mea-
surable. Inverse agonists bind to these receptors and greatly reduce the incidence of
the active conformation responsible for this constitutive activity, as a result inverse
agonists appear to exert an opposite effect to the agonist. The difference between