Agonists, partial agonists, antagonists, inverse agonists and agonist/antagonists?

doi:10.1016/0165-6147(87)90229-X

Trends in Pharmacological Sciences

Volume 8, Issue 11, November 1987, Pages 423-426

https://doi.org/10.1016/0165-6147(87)90229-X Get rights and content

Abstract

The label placed on a drug influences its ultimate use. But interpretation ofin-vivo data has complicated the simple receptor theory of agonists and antagonists for certain classes of drugs.Terry Kenakin argues that clarification of such data — described in an extremely complex system — at a molecular level, will either obviate the need for terms such as inverse agonist or agonist/antagonist, or result in the rewriting of the classical receptor theory.

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Citation Excerpt :
However, the above dogmatism about receptors seems to have vanished with the realization that even in the absence of agonists, many systems display “spontaneous activity” (Costa and Herz, 1989), while mutated receptors might be or become “constitutively active” (Kenakin, 1995; Milligan and Bond, 1997), and could explain the behavior of inverse agonists (Bond et al., 1995; Kenakin, 1994). Understandably, during this paradigm shift, the discoveries and recognition of spontaneous receptor activity briefly confused the definition of what agonists and antagonists should be, how to designate them, and furthermore, how to design experiments (Hoyer and Boddeke, 1993; Jenkinson, 1991; Kenakin, 1987). In those years, new notions and formulations were introduced, for example, concepts appeared such as “inverse agonism,” “negative efficacy,” and “negative intrinsic activity” as well as “negative antagonism” (Bond et al., 1995; Costa et al., 1992; Kenakin, 1994, 1995; Milligan et al., 1995; Samama et al., 1993).
Increasing numbers of compounds, previously classified as antagonists, were shown to inhibit this spontaneous or constitutive receptor activity, instead of leave it unaffected as expected for a formal antagonist. In addition, some other antagonists did not have any effect by themselves, but prevented the inhibition of constitutive activity induced by thought-to-be antagonists. These thought-to-be antagonists with negative efficacy are now known as “inverse agonists.”
Inverse agonism at βAR has been evidenced for both subtypes in wild-type GPCRs systems and in engineered systems with high constitutive activity. It is important to mention that native systems are of particular importance for analyzing the in vivo relevance of constitutive activity because these systems have physiological expression levels of target receptors. Studies of inverse agonism of β blockers in physiological setting have also evidenced that pathophysiological conditions can affect pharmacodynamic properties of these ligands.
To date, hundreds of clinically well-known drugs have been tested and classified for this property. Prominent examples include the beta-blockers propranolol, alprenolol, pindolol, and timolol used for treating hypertension, angina pectoris, and arrhythmia that act on the β₂ARs, metoprolol, and bisoprolol used for treating hypertension, coronary heart disease, and arrhythmias by acting on β₁ARs. Inverse agonists seem to be useful in the treatment of chronic disease characterized by harmful effects resulting from β₁AR and β₂AR overactivation, such as heart failure and asthma, respectively.
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Trends in Pharmacological Sciences

ViewpointAgonists, partial agonists, antagonists, inverse agonists and agonist/antagonists?

Abstract

J. Theoret. Biol.

Science

J. Pharmacol. Exp. Ther.

Pharmacol. Rev.

J. Pharmacol. Exp. Ther.

J. Pharmacol. Exp. Ther.

J. Pharmacol. Exp. Ther.

Pharmacol. Rev.

Viewpoint
Agonists, partial agonists, antagonists, inverse agonists and agonist/antagonists?