Agonist drugs bind to and activate the receptor in some fashion, which directly or indirectly brings about the effect (Figure 1–2A). Receptor activation involves a change in conformation in the cases that have been studied at the molecular structure level. Some receptors incorporate effector machinery in the same molecule, so that drug binding brings about the effect directly, eg, opening of an ion channel or activation of enzyme activity. Other receptors are linked through one or more intervening coupling molecules to a separate effector molecule. The major types of drug-receptoreffector coupling systems are discussed in Chapter 2. Pharmacologic antagonist drugs, by binding to a receptor, compete with and prevent binding by other molecules. For example, acetylcholine receptor blockers such as atropine are antagonists because they prevent access of acetylcholine and similar agonist drugs to the acetylcholine receptor site and they stabilize the receptor in its inactive state (or some state other than the acetylcholine-activated state). These agents reduce the effects of acetylcholine and similar molecules in the body (Figure 1–2B), but their action can be overcome by increasing the dosage of agonist. Some antagonists bind very tightly to the receptor site in an irreversible or pseudoirreversible fashion and cannot be displaced by increasing the agonist concentration. Drugs that bind to the same receptor molecule but do not prevent binding of the agonist are said to act allosterically and may enhance (Figure 1–2C) or inhibit (Figure 1–2D) the action of the agonist molecule. Allosteric inhibition is not usually overcome by increasing the dose of agonist.
B. Agonists That Inhibit Their Binding Molecules
Some drugs mimic agonist drugs by inhibiting the molecules responsible for terminating the action of an endogenous agonist. For example, acetylcholinesterase inhibitors, by slowing the destruction of endogenous acetylcholine, cause cholinomimetic effects that closely resemble the actions of cholinoceptor agonist molecules even though cholinesterase inhibitors do not bind or only incidentally bind to cholinoceptors (see Chapter 7). Because they amplify the effects of physiologically released agonist ligands, their effects are sometimes more selective and less toxic than those of exogenous agonists.
C. Agonists, Partial Agonists, and Inverse Agonists
Figure 1–3 describes a useful model of drug-receptor interaction. As indicated, the receptor is postulated to exist in the inactive, nonfunctional form (Ri) and in the activated form (Ra). Thermodynamic considerations indicate that even in the absence of any agonist, some of the receptor pool must exist in the Ra form some of the time and may produce the same physiologic effect as agonist-induced activity. This effect, occurring in the absence of agonist, is termed constitutive activity. Agonists have a much higher affinity for the Ra configuration and stabilize it, so that a large percentage of the total pool resides in the Ra–D fraction and a large effect is produced. The recognition of constitutive activity may depend on the receptor density, the concentration of coupling molecules (if a coupled system), and the number of effectors in the system.