Spare receptors, partial agonists, and ternary complex model of drug action.
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.
D000316:Adrenergic alpha-Agonists / Q000378:metabolism* / Q000502:physiology; D000818:Animals; D006801:Humans; D008954:Models, Biological; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000502:physiology*; D011942:Receptors, Adrenergic, alpha / Q000378:metabolism* / Q000502:physiology; D014661:Vasoconstriction
D000316:Adrenergic alpha-Agonists; D011942:Receptors, Adrenergic, alpha