Piperazinyl carbamate fatty acid amide hydrolase inhibitors and transient receptor potential channel modulators as "dual-target" analgesics

tWe showed previously that inhibiting fatty acid amide hydrolase (FAAH), an endocannabinoid degrad-ing enzyme, and transient receptor potential vanilloid type-1 (TRPV1) channels with the same molecule,the naturally occurring N-arachidonoyl-serotonin (AA-5-HT), produces more efficacious anti-nociceptiveand anti-hyperalgesic actions than the targeting of FAAH or TRPV1 alone. We also reported the syn-thesis of some piperazinyl carbamates as “dual” FAAH inhibitors and either antagonists at TRPV1 oragonists/desensitizers of the transient receptor potential ankyrin type-1 (TRPA1) cannel, another targetfor analgesic drugs. We investigated here if two such compounds, the FAAH/TRPV1 blocker OMDM198and the FAAH inhibitor/TRPA1 agonist, OMDM202, exert anti-nociceptive actions in the formalin test ofpain in mice, and through what mechanism. Both compounds inhibited the second phase of the responseto formalin, the effect being maximal at 3 mg/kg, i.p. Antagonism of CB1 or CB2 receptors with AM251 orAM630 (1 mg/kg, i.p.), respectively, reversed this effect. A TRPV1 agonist, palvanil (0.1 mg/kg, i.p.), alsoreversed the analgesic effect of OMDM198. OMDM202 action was also antagonized by a per se inactivedose of the selective TRPA1 blocker, AP-18 (0.05 mg/kg, i.p.), but not by a TRPV1 antagonist. AP-18 athigher doses (0.1–0.2 mg/kg) inhibited both the first and second phase of the formalin response. Theeffects of OMDM198 and OMDM202 were accompanied by elevation of anandamide levels in the spinalcord. OMDM198 (0.1–5.0 mg/kg, i.p.) also reversed carrageenan-induced oedema and thermal hyper-algesia in mice with efficacy similar to that of AA-5-HT. These data suggest that “dual” fatty acid amidehydrolase and transient receptor potential channel modulators should be clinically evaluated as novelanalgesics.