How Spare Receptors Oppose the Action of Certain Antagonists

Some non-competitive antagonists appear to be more effective in opposing the actions of partial agonists than in opposing full agonists. The full agonist appears to be partially protected. A ternary complex model of drug action offers a possible explanation of such phenomena. We assume that binary receptor-ligand complex must bind to an activator to form a ternary complex and the phenomenological activity is proportional to the ternary binary complex of full agonists binds tightly to the activator while the binary complex of partial agonists binds less firmly to the activator. Noncompetitive antagonists which reduce the affinity of the binary complex to the activator will cause a reduction in maximum response and a rightward shift in the ED50 of partial agonists. By contrast the activity of a full agonist in a system possessing more receptor molecules than activator molecules spare receptors may be less altered when exposed to the antagonist. The maximum response of the full agonist may be only slightly reduced by the antagonist while the ED50 is shifted more noticeably to the right. Removing a large portion of the receptors may make the dose response curve to the full agonist resemble that of a partial agonist resemble that of a partial agonist and induce full sensitivity to the antagonist. The qualitative features of this system resemble the blood pressure responses of pithed rats to alpha-1 adrenergic agonists in the presence of calcium blockers. Keywords Alpha-I receptors, Calcium blockers, G-protein, Adrenergic receptor theory, Non-competitive antagonist. Author.