Coincubation no receptor reserve

A rightward shift of the dose-response curves (Figure 224) without decrease in the maximal response can be observed for competitive antagonists (Figure 226). They compete for binding to the same or to partially overlapping sites at the receptor so that the binding of the one excludes the binding of the other. They produce a rightward shift of the agonist dose-response curve without affecting the maximal response. The shift increases with the antagonist concentration and is, in principle, unlimited. Based on these shifts, the antagonist affinity can be calculated by the Schild method.

A decrease in the maximal response (Figure 225) can be observed for different classes of non-competitive antagonists (Figures 226 and 227):

• Allosteric antagonists (Figure 226) bind to a site of the receptor that is topographically different from the orthosteric binding site. They are non-competitive since they do not compete with the agonist for binding to the orthosteric site. Allosteric antagonists may decrease the efficacy (and eventually also the potency) of the agonist (see Section 4.14).

Receptor Reserve

LogfagonJst concentration) Log(agonist concentration)

Figure 225 Antagonists are denoted as (non)-competitive or (in)surmountable depending on the incubation protocol. Co-incubation experiments: antagonists are non-competitive if the maximal response decreases and are usually competitive if the agonist dose-response curve is shifted to the right without limit.

LogfagonJst concentration) Log(agonist concentration)

Figure 225 Antagonists are denoted as (non)-competitive or (in)surmountable depending on the incubation protocol. Co-incubation experiments: antagonists are non-competitive if the maximal response decreases and are usually competitive if the agonist dose-response curve is shifted to the right without limit.

• Functional antagonists (Figure 226) block an intracellular event that is triggered by the agonist-receptor interaction and thereby impair the chain of events linking the stimulus to the measured response. These antagonists do not bind to the receptor (and thus do not block agonist binding and receptor activation). Since a particular response may be triggered by a variety of different receptors in the same tissue (e.g. a-adrenergic, angiotensin II, Neuropeptide Y, serotonin, prostaglandin and endothelin receptors trigger vascular smooth muscle contraction), functional antagonists are likely to block the responses of all these receptors. Therefore, if an antagonist is found to be non-competitive for a given receptor, its ability to affect the action of related receptors (i.e. giving the same response) is usually checked to find out whether it is a functional antagonist or not. In radioligand binding experiments, functional antagonists are unlikely to affect the binding of orthosteric ligands, as they do not directly interact with the receptor. However, an

Non Competitive Antagonism
Figure 226 Molecular mechanisms resulting in competitive versus non-competitive antagonism.
Receptor Reserve

Figure 227 Relationship between (non)-competitive and (in)surmountable antagonists. Reprinted from Angiotensin II Receptor Antagonists (M. Epstein and H.R. Brunner, Eds.), Vauquelin G., Fierens F.L.P. and Vanderheyden P.M.L., Mechanisms of Angiotensin II Antagonism. Competitive versus Non-Competitive Inhibition, pp. 105-118. Copyright (2002), with permission from Elsevier.

Figure 227 Relationship between (non)-competitive and (in)surmountable antagonists. Reprinted from Angiotensin II Receptor Antagonists (M. Epstein and H.R. Brunner, Eds.), Vauquelin G., Fierens F.L.P. and Vanderheyden P.M.L., Mechanisms of Angiotensin II Antagonism. Competitive versus Non-Competitive Inhibition, pp. 105-118. Copyright (2002), with permission from Elsevier.

exception should be made for those antagonists that bind to G proteins and impair their coupling to the receptor.

It is important to note that a decrease in the maximal response of an agonist only refers to non-competitive antagonism when both ligands are added together to the receptor (i.e. co-incubation, Figure 227). It is only under these conditions that agonists and antagonists are given an equal chance to compete with each other for binding to the receptor.

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