Review
Mechanisms of inverse agonism at G-protein-coupled receptors

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Abstract

Many drugs with important therapeutic actions that had been assumed to be antagonists at G-protein-coupled receptors (GPCRs) have been shown to be inverse agonists. For both basic pharmacology and drug design it is important to understand the mechanisms whereby these drugs achieve their effects. It had been assumed that these drugs achieved their effects by stabilizing an inactive state of the receptor (R) at the expense of a partially activated state (R*). In this article, I consider this and other mechanisms that could explain inverse agonist actions, and conclude that more than one mechanism can apply to inverse agonism at GPCRs.

Section snippets

The spectrum of efficacy

Although a few years ago it was thought that drugs acting at GPCRs could be divided into two classes, agonists and antagonists, it now seems that for most GPCRs the compounds acting at these receptors exhibit a spectrum of efficacy from inverse agonism through neutral antagonism to agonism. In the same way as agonists can exhibit a spectrum of activity from low-intrinsic-activity partial agonists to full agonists so can inverse agonists. Full and partial inverse agonists have been described in

Physiological relevance of inverse agonism

Many drugs that had previously been considered to be antagonists have subsequently been shown to be inverse agonists in some assay systems. It is important to ask whether this matters in terms of drug effects in humans or animals. Many descriptions of inverse agonism rely on effects in recombinant systems but it is important to examine effects in native tissues. Acute administration of inverse agonists to native tissues might be expected to suppress the basal (agonist-independent) activity of a

Mechanisms of inverse agonism

Thus, inverse agonists might exert their effects either acutely or chronically. Understanding the mechanism of the effects of inverse agonists is important because it could provide new ways to design drugs of defined intrinsic activity. During activation of ionotropic receptors, these receptors undergo a series of allosteric transitions between different conformational states [16] so that inverse agonists presumably stabilize certain states of the receptor with different functional activities.

Stabilization of the R state of the receptor by inverse agonists at the expense of the R* state

One of the first tests of the proposal that inverse agonists stabilize the R state of the receptor at the expense of the R* receptor state was to use certain mutants of GPCRs that were thought to favour the R* state, the so-called constitutively active mutants [17]. If the R* state is favoured for these mutants and the inverse agonist binds preferentially to R over R*, it might be assumed that the affinity of the inverse agonist would be reduced by the mutation. However, this is a rather

Stabilization of the R state over the R*G state

One of the earliest descriptions of inverse agonism for GPCRs was for opiate receptors 25, 26. It was suggested that inverse agonists were switching the receptor between the RG and R states of the receptor. This depended on the sensitivity of the binding of inverse agonists to the effects of guanine nucleotides. Agonist affinity was decreased by GTP whereas inverse agonist affinity was increased and it was assumed that GTP was destabilizing the RG state. It was suggested that whereas agonists

Radiolabelled agonist and inverse agonist binding

It is important to consider the use of another tool for probing the mechanism of inverse agonism that is related to the effects of guanine nucleotides described above. This concerns the evaluation of inverse agonist affinity in competition studies versus radiolabelled agonist binding and versus radiolabelled inverse agonist binding (Box 3). If the extended ternary complex model holds for the system concerned, a radiolabelled agonist should label the R*G state with high affinity. A radiolabelled

Concluding remarks

Inverse agonism can be achieved by more than one mechanism. For some compounds there is evidence that inverse agonism is achieved by the stabilization of the R state of the receptor over the R* state. For other compounds there is no redistribution of the different affinity states of the receptor but the inverse-agonist–receptor complex is inactive. This suggests that different inverse agonists stabilize a receptor in different conformations with different functional consequences.

Chemical name

Acknowledgements

I thank David Hall and Sam Hoare for their insightful comments on this paper.

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