A Double Whammy: Targeting Both Fatty Acid Amide Hydrolase (FAAH) and Cyclooxygenase (COX) To Treat Pain and Inflammation

Abstract

Pain states that arise from non-resolving inflammation, such as inflammatory bowel disease or arthritis, pose an unusually difficult challenge for therapy because of the complexity and heterogeneity of their underlying mechanisms. It has been suggested that key nodes linking interactive pathogenic pathways of non-resolving inflammation might offer novel targets for the treatment of inflammatory pain. Non-steroidal anti-inflammatory drugs (NSAIDs), which inhibit the cyclooxygenase (COX)-mediated production of pain- and inflammation-inducing prostanoids, are a common first-line treatment for this condition, but their use is limited by mechanism-based side effects. The endogenous levels of anandamide, an endocannabinoid mediator with analgesic and tissue protective functions, are regulated by fatty acid amide hydrolase (FAAH). The present article outlines the pharmacological and chemical rationale for the simultaneous inhibition of COX and FAAH activities with designed multi-target agents. Preclinical studies indicate that such agents may combine superior anti-inflammatory efficacy with reduced toxicity.

Structure–activity relationships for the synthesis of selective cyclooxygenase 2 inhibitors: an overview (2009–2016)

“…13 However, there is growing interest towards dual molecules such as FAAH/TRPV1 blockers and also FAAH/COX-2 inhibitors; 14 specifically, it is shown how COX-2-mediated transformation of anandamide into pro-algesic prostamides has led to the hypothesis of the presence of deeper functional connections between the endocannabinoid and prostanoid systems. 15 The interest in COX-2 inhibition has been emphasized by the fact that it is often involved in oxidative stress 16 and also in cancer progression. In fact, studies have demonstrated how prediagnostic use of NSAIDs, such as aspirin, and selective COX-2 inhibitors was, however, associated with a reduced rate of breast cancer recurrence.…”

Lignans from <i>Morinda citrifolia</i> (Noni) Fruit Inhibit Fatty Acid Amide Hydrolase and Monoacylglycerol Lipase <i>in Vitro</i>

“…Several of these lignans displayed significant cyclooxygenase (COX) and lipoxygenase (LOX) inhibiting activity [16]. Other COX inhibitors have also been found to influence endocannabinoid catabolism [17]. Therefore, we focused on lignans from noni fruit in our assays, including morindolin, isoprincepin, 3,3'-bisdemethylpinoresinol, americanin A, americanoic acid A.…”

TRP Channels as Novel Targets for Endogenous Ligands: Focus on Endocannabinoids and Nociceptive Signalling

“…Thus, it is not surprising that targeting the endocannabinoid system is suggested as a promising treatment opportunity for a number of pathological states. To mention just a few recent reviews, related to the nervous system only, these include anxiety and depressive symptoms [ 33 , 34 ]; Alzheimer's disease [ 35 ]; schizophrenia [ 36 - 38 ]; pain and inflammation [ 9 , 39 , 40 ]; multiple sclerosis [ 41 ]; stroke and brain trauma [ 42 ]; Parkinson's disease [ 43 ]; epilepsy [ 44 ] and addiction [ 45 ].…”

“…By engaging the native protective cell signalling pathways, endocannabinoids (eCBs) as well as related phytocannabinoids can be promising candidates for the treatment of chronic pain since they possess low toxicity and low addiction potential. In this regard, inhibitors of enzymes (for example, fatty acid amide hydrolase (FAAH)) that hydrolyze eCBs are of particular interest [ 9 ].…”