New N-Arachidonoylserotonin Analogues with Potential “Dual” Mechanism of Action against Pain

Abstract

N-arachidonoylserotonin (AA-5-HT, 1a) is an inhibitor of fatty acid amide hydrolase (FAAH) that acts also as an antagonist of transient receptor potential vanilloid-type 1 (TRPV1) channels and is analgesic in rodents. We modified the chemical structure of 1a with the aim of developing "hybrid" FAAH/TRPV1 blockers more potent than the parent compound or obtaining analogues with single activity at either of the two targets to study the mechanism of the analgesic action of 1a. Thirty-eight AA-5-HT analogues, containing a serotonin "head" bound to a variety of lipophilic moieties via amide, urea, or carbamate functionalities, were synthesized. Unlike 1a, most of the new compounds possessed activity at only one of the two considered targets. The amides 1b and 1c of alpha- and gamma-linolenic acid, however, showed "hybrid" activity similar to 1a. The carbamate 3f (OMDM106), although unable to antagonize TRPV1 receptors, was the most potent FAAH inhibitor in this study (IC50=0.5 microM). Compounds 3f and 1m (OMDM129), which exhibited activity at only FAAH or TRPV1, respectively, were 10-fold less potent than 1a at preventing formalin-induced hyperalgesia in mice.

The Endocannabinoid System and its Modulation by Phytocannabinoids

“…Nevertheless, the abovementioned thermo-TRPs, especially in the absence of other strong and specific exogenous/xenobiotic modulators, are now considered by all means bona fide "ionotropic cannabinoid receptors", whereas CB 1 R and CB 2 R would thus be defined as "metabotropic cannabinoid receptors" [3,17,18]. Importantly, several "endocannabinoid-like" mediators, such as, on the one hand, the anandamide congeners N-palmitoylethanolamine, N-oleoylethanolamine, and N-linoleoylethanolamine, as well as several N-acyl-dopamines and N-acyl-taurines, as direct or indirect activators [11,[19][20][21][22], and, on the other hand, some N-acyl-serotonins, as competitive antagonists [23,24], have been shown to interact with TRPV1 in in vitro and in vivo studies.…”

Anxiolytic Effects in Mice of a Dual Blocker of Fatty Acid Amide Hydrolase and Transient Receptor Potential Vanilloid Type-1 Channels

“…One such dual FAAH/TRPV1 blocker is N-arachidonoyl-serotonin (AA-5-HT) (Bisogno et al, 1998;Maione et al, 2007), which exerts antihyperalgesic effects by inactivating both proteins (Maione et al, 2007;Ortar et al, 2007). As strain differences, possibly due to neuroanatomical, neurochemical, or genetic factors, exist in mice for their sensitivity to antidepressant or anxiolytic compounds (Crawley et al, 1997;Griebel et al, 2000;Lepicard et al, 2000;Leggio et al, 2008), we investigated here the potential anxiolytic effect of AA-5-HT (and, as a comparison, of diazepam) in both C57BL/6J and Swiss mice, using the EPM, a well-validated test to search for new anxiolytic agents (Pellow et al, 1985;File, 1992).…”

The multiplicity of spinal AA-5-HT anti-nociceptive action in a rat model of neuropathic pain

“…In previous studies, AA-5-HT was chronically administered subcutaneously or i.p. and as it is easily metabolised, its interaction with these tissues could not be distinguished [22,50,58] and had remained poorly understood.…”