BACKGROUND AND PURPOSE:

Prostamides are emerging lipid mediators formed from cycloxygenase-2 (COX-2)-catalysed oxidation of the endocannabinoid anandamide. They produce effects that are often opposite to those caused by cannabinoid receptor activation by anandamide. COX-2-mediated oxygenation of anandamide may occur when hydrolysis of this compound by fatty acid amide hydrolase (FAAH) is physiologically, pathologically or pharmacologically reduced. Thus, the therapeutic properties of FAAH inhibitors might be attenuated by the concomitant production of prostamide F_2α , which acts at specific receptors.

EXPERIMENTAL APPROACH:

We investigated whether a series of synthetic compounds designed to selectively antagonize prostamide versus prostanoid receptors, could also inhibit FAAH. Among these compounds were the previously described selective prostamide antagonists AGN 204396, AGN 211335 and AGN 211336.

KEY RESULTS:

The prostamide F_2α receptor antagonists were active against mouse and rat FAAH in the low μM range of concentrations They appeared to behave as non-competitive and plasma membrane-permeant inhibitors of the enzyme. AGN 211335, the most potent against rat FAAH of these compounds (IC₅₀ = 1.2 μM), elevated exogenous anandamide levels in intact cells, and also exhibited affinity for cannabinoid CB₁receptors. Both AGN 211335 and AGN 211336 (0.25-1 mg kg^-1 , i.p.) inhibited the formalin-induced nociceptive response in mice.

CONCLUSIONS:

These findings suggest that synthetic compounds with indirect agonist activity at cannabinoid receptors and antagonistic activity at prostamide receptors can be developed. Such compounds could be used in the future as an alternative to selective FAAH inhibitors to prevent a potential consequence of FAAH inhibition, namely prostamide F_2α -induced inflammation and pain.
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PMID:

 

24102214

 

[PubMed – as supplied by publisher]