Agonism, inverse

The most probable mechanism for inverse agonism is the same one operable for positive agonism namely, selective receptor state affinity. However, unlike agonists that have a selectively higher affinity for the receptor active state (to induce G-protein activation and subsequent physiological response) inverse agonists have a selectively higher affinity for the inactive receptor state and thus uncouple already spontaneously coupled [RaG] species in the system. 

The discovery of constitutive receptor activity uncovered a major new idea in receptor pharmacology namely, the concept of negative efficacy and inverse agonism. 

Negative efficacy, by definition, efficacy is that property of a molecule that causes the receptor to change its behavior toward the biological host. Negative efficacy refers to the property of selective affinity of the molecule for the inactive state of the receptor this results in inverse agonism. Negative efficacy causes the active antagonism of constitutive receptor activity but is only observed in systems that have a measurably elevated basal response due to constitutive activity. It is a property of the molecule and not the system. 

Intercellular adhesion molecule-1, 128 Interfacial inhibition, 159 Intrinsic activity, 44-46 Intrinsic efficacy, 9, 45, 115 Inverse agonism, 49, 108 Inverse agonists... 

A receptor system must be constitutively active (elevated basal response) to detect inverse agonism (Fig. 1). In nonconstitutively active receptor systems, inverse agonists behave as simple competitive antagonists. 

Dysfunction of the GABAa receptor complex such that the effects of all benzodiazepine receptor ligands are shifted in the direction of inverse agonism. In this case, fiumazenil (which normally has zero efficacy) should induce anxiety in anxious patients but have no effects in healthy subjects because they have normal receptors. 

Figure 19.8 A schematic representation of the GABAa receptor shift hypothesis. This proposes that patients with panic disorder have dysfunctional GABAa receptors such that the actions of drugs that behave as antagonists in normal subjects are expressed as inverse agonism in panic patients. It is unlikely that this theory extends to generalised anxiety disorder (GAD), for which benzodiazepine agonists are highly effective treatments, but it could explain why these drugs are relatively ineffective at treating panic disorder. (Based on Nutt et al. 1990)...

The 4-fluoro (518), 4-trifluoromethyl (523) and 3-chloro derivatives (522) also showed improved binding. 3,5-Disubstitution was also well tolerated (519), however the 3,4-difluoro compound (521) had the most potent inverse agonism of the series with an EC50 of 8 uM, with an average 110% maximal response and 400-fold selectivity over CB2. In addition to the crucial role of the 4-chloro substituent on the 5-phenyl ring, the 2,4-dichloro substitution on the 6-phenyl ring, which mimics that of (382), was also found to be optimal. 

Agonism and Inverse Agonism Are the Basic Properties of Ligands Alone... 

It should be noted that inverse agonism can only be appreciated in receptor systems where the constitutive activity is measurable and therefore can be observed to decrease. Thus, neutral antag-... 

Bakker, R. A., Wieland, K., Timmerman, H. Leurs, R. (2000). Constitutive activity of the histamine H(l) receptor reveals inverse agonism of histamine H(l) receptor antagonists. Eur. J. Pharmacol. 387, R5-7. 

Leurs, R., Church, M. K Taglialatela, M. (2002). Hl-antihistamines inverse agonism, anti-inflammatory actions and cardiac effects. Clin. Exp. Allergy 32, 489-98. 

Smit, M. J., Leurs, R., Alewijnse, A. E. et al. (1996). Inverse agonism of histamine H2 antagonist accounts for upregulation of spontaneously active histamine H2 receptors. Proc. Natl. Acad. Sci. USA 93, 6802-7. 

Gentil Y, Tavares S, Gorenstein C, Bello C, Mathias L, Gronich G and Singer J (1990). Acute reversal of flunitrazepam effects by Ro 15-1788 and Ro 15-3505 Inverse agonism, tolerance and rebound. Psychopharmacology, 100, 54—59. 

Wieland, K., Bongers, G., Yamamoto, Y. etal. Constitutive activity of histamine H3 receptors stably expressed in SK-N-MC cells display of agonism and inverse agonism by H3 antagonists. /. Pharmacol. Exp. Ther. 299 908-914, 2001. 

Rossier, O., Abuin, L., Fanelli, F., Leonardi, A. and Cotecchia, S. (1999) Inverse agonism and neutral antagonism at alpha(la)- and alpha(lb)-adrenergic receptor subtypes. Molecular Pharmacology, 56, 858-866. 

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