Elsevier

Biochemical Pharmacology

Volume 71, Issue 12, 14 June 2006, Pages 1663-1670
Biochemical Pharmacology

Commentary
Some implications of receptor theory for in vivo assessment of agonists, antagonists and inverse agonists

https://doi.org/10.1016/j.bcp.2005.12.038Get rights and content

Abstract

Drug effects can be classified into three major phenotypes: agonist, antagonist and inverse agonist. Agonist and inverse agonist effects are associated with receptor activation and inactivation, respectively, whereas antagonism implies that a drug produces no effect when administered alone but blocks the effects of agonists and inverse agonists. Attention has only recently begun to focus on the theoretical and clinical implications of inverse agonists, and studies of inverse agonism have also stimulated revisions in receptor theory. This commentary addresses two specific issues related to the application of receptor theory to studies of inverse agonists in vivo. First, principles of receptor theory suggest that increasing drug doses produce a graded pharmacological stimulus that is transduced by receptor-containing tissue into a biological response. However, assays vary in their ability to detect those responses, and any given assay provides only a narrow window on the full range of underlying drug effects. Consequently, in vivo assessment of inverse agonists will benefit from development of assays sensitive to graded inverse agonist effects. Second, detection of inverse agonist effects requires some preexisting level of receptor activity (or tone). This tone can result from at least two sources: (a) endogenous ligands for the receptor, or (b) constitutive receptor activity. Strategies for discriminating these two sources of tone will also contribute to the in vivo assessment of inverse agonist effects. Studies with intermediate efficacy ligands may be especially helpful in this regard, because their effects are differentially influenced by endogenous agonist tone versus constitutive receptor tone.

Section snippets

Constraints on response detection as a determinant of drug effects

First, this model supposes that the tissue is able to generate graded effects across all drug doses from the lowest active dose sufficient to bind a single receptor to a maximal dose that binds all receptors. Moreover, this model supposes the existence of an experimental procedure that can detect and differentiate effects across this entire range. In practice, neither premise holds [7]. Some threshold level of tissue response is required before a signal can be detected by the experimental

Preexisting receptor activity (tone) as a determinant of drug effects

A second simplification of the original model of occupation theory lies in its assumption that target receptors in a tissue are quiescent prior to delivery of the drug. Again, though, this premise does not appear to hold under many circumstances. Rather, drug effects on receptor activity are often integrated with some preexisting level of receptor activity, which can be referred to as the “tone” of the receptor system. There are at least two sources of tone, and of interest for the present

Implications

The ability of drugs to produce agonist, antagonist or inverse agonist effects in vivo depends not only on features inherent to the drug, but also on characteristics of the assay system and on the magnitude and source of preexisting levels of receptor activity, or tone. The dependence of drug phenotypes on tissue and assay conditions indicates that, at the very least, care should be taken to cultivate an awareness of the constraints that any particular assay imposes on the detection of

Acknowledgement

This work was supported in part by R01-DA11460 from the National Institute on Drug Abuse, NIH.

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