Prostamide F2α receptor antagonism combined with inhibition of FAAH may block the pro‐inflammatory mediators formed following selective FAAH inhibition. (March 2014)

• Record Type: Journal Article
• Authors: Ligresti, Alessia; Martos, Jose; Wang, Jenny; Guida, Francesca; Allarà, Marco; Palmieri, Vittoria; Luongo, Livio; Woodward, David; Di Marzo, Vincenzo
• Is Part Of: British journal of pharmacology. Volume 171:Number 6(2014:Mar.)
• Page Start: 1408
• Page End: 1419
• Publication Date: 2014-03
• Subjects: Pharmacology -- Periodicals; Chemotherapy -- Periodicals; Drug Therapy -- Periodicals; Pharmacology -- Periodicals; 615.1
• DOI: 10.1111/bph.12410
• Languages: English
• ISSNs: 0007-1188

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="bph12410-sec-0001" sec-type="section"> <title>Background and Purpose</title> <p>Prostamides are lipid mediators formed by COX‐2‐catalysed oxidation of the endocannabinoid anandamide and eliciting effects often opposed to those caused by anandamide. Prostamides may be formed when hydrolysis of anandamide by fatty acid amide hydrolase (FAAH) is physiologically, pathologically or pharmacologically decreased. Thus, therapeutic benefits of FAAH inhibitors might be attenuated by concomitant production of prostamide F<sub>2</sub><sub>α</sub>. This loss of benefit might be minimized by compounds designed to selectively antagonize prostamide receptors and also inhibiting FAAH.</p> </sec> <sec id="bph12410-sec-0002" sec-type="section"> <title>Experimental Approach</title> <p>Inhibition of FAAH by a series of selective antagonists of prostamide receptors, including AGN 204396, AGN 211335 and AGN 211336, was assessed using rat, mouse and human FAAH <italic>in vitro</italic>, together with affinity for human recombinant CB<sub>1</sub> and CB<sub>2</sub> receptors. Effects <italic>in vivo</italic> were measured in a model of formalin‐induced inflammatory pain in mice.</p> </sec> <sec id="bph12410-sec-0003" sec-type="section"> <title>Key Results</title> <p>The prostamide F<sub>2</sub><sub>α</sub> receptor antagonists were active against mouse and rat FAAH in the low μM range and behaved as non‐competitive and plasma membrane‐permeant inhibitors. AGN 211335, the most potent inhibitor of rat FAAH (IC<sub>50</sub> = 1.2 μM), raised exogenous anandamide levels in intact cells and also bound to cannabinoid CB<sub>1</sub> receptors. Both AGN 211335 and AGN 211336 (0.25–1 mg·kg<sup>−1</sup>, i.p.) inhibited the formalin‐induced nociceptive response in mice.</p> </sec> <sec id="bph12410-sec-0004" sec-type="section"> <title>Conclusions and Implications</title> <p>Synthetic compounds with indirect agonist activity at cannabinoid receptors and antagonist activity at prostamide receptors can be developed. Such compounds could be used as alternatives to selective FAAH inhibitors to prevent the possibility of prostamide F<sub>2</sub><sub>α</sub>‐induced inflammation and pain.</p> </sec> <sec id="bph12410-sec-5001" sec-type="relatedArticles"> <title>Linked Articles</title> <p>This article is part of a themed section on Cannabinoids 2013. To view the other articles in this section visit <ext-link ext-link-type="doi" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink">http://dx.doi.org/10.1111/bph.2014.171.issue‐6</ext-link></p> </sec> </abstract>