Prostamide F2α receptor antagonism combined with inhibition of FAAH may block the pro‐inflammatory mediators formed following selective FAAH inhibition

• DOI: 10.1111/bph.12410
• Publication Date: 2013-10-08T15:12:47Z
• Authors: Alessia Ligresti; Jose Martos; Jenny Wang; Francesca Guida; Marco Allarà; Vittoria Palmieri; Livio Luongo; David Woodward; Vincenzo Di Marzo
• Keywords: 0303 health sciences; Molecular Sequence Data; Receptors, Prostaglandin; Dinoprostone; 3. Good health; Amidohydrolases; Mice; 03 medical and health sciences; HEK293 Cells; Cats; anandamide; endocannabinoid; FAAH; pain; PGs; prostamides; Amidohydrolases; Animals; Cats; Dinoprostone; Enzyme Inhibitors; HEK293 Cells; Humans; Inflammation Mediators; Mice; Molecular Sequence Data; Receptors, Prostaglandin; Pharmacology; Animals; Humans; Enzyme Inhibitors; Inflammation Mediators

Background and PurposeProstamides 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 F2α. This loss of benefit might be minimized by compounds designed to selectively antagonize prostamide receptors and also inhibiting FAAH.Experimental ApproachInhibition 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 in vitro, together with affinity for human recombinant CB1 and CB2 receptors. Effects in vivo were measured in a model of formalin‐induced inflammatory pain in mice.Key ResultsThe prostamide F2α 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 (IC50 = 1.2 μM), raised exogenous anandamide levels in intact cells and also bound to cannabinoid CB1 receptors. Both AGN 211335 and AGN 211336 (0.25–1 mg·kg−1, i.p.) inhibited the formalin‐induced nociceptive response in mice.Conclusions and ImplicationsSynthetic 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 F2α‐induced inflammation and pain.Linked ArticlesThis article is part of a themed section on Cannabinoids 2013. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue‐6