AJP - Endocrinology and Metabolism, Vol 253, Issue 1 E114-E121, Copyright © 1987 by American Physiological Society
Spare receptors, partial agonists, and ternary complex model of drug action
L. D. Homer and T. B. Nielsen
The occurrence of spare receptors and partial agonists for smooth muscle
contractions mediated by alpha 1-adrenergic receptors can be accounted for
with a ternary complex model of drug action presented here. In this model,
receptor-ligand complexes are assumed to be inactive until the complex
binds to an activating protein. Contractile responses are assumed to be
proportional to the concentration of ternary complex
(receptor-ligand-activator) regardless of the ligand involved. Antagonists
are unable to form the ternary complex. Spare receptors are present as the
inactive receptor-ligand complex. Such a model is shown to fit already
published data on membrane binding of alpha 1-adrenergic agonists as well
as contractile responses to the agonist. Schild plots are expected to
resemble those of a single-site model of drug action. The double-reciprocal
plots of receptor-inactivation studies will display only a slight curvature
as may be seen in previously published articles. Partial agonists may have
50% response doses lowe or higher than full agonists. The hypothesis that
ternary complexes are formed with alpha 1-receptors could be tested more
critically with receptor-inactivation studies using both antagonists and
agonists. Partial inactivation of receptor and activator protein should
reduce the binding of antagonist without altering the concentration needed
to bind to 50% of the receptors. On the other hand, the concentration of
agonist required to displace 50% of a bound antagonist is expected to
increase. The proposal that contractile responses are proportional to the
ternary complex concentration could be tested by fitting the ternary
complex model to the data from studies of contractions induced by partial
agonists as well as full agonists.
