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

• Published in: Pharmacological research 2013-10, Vol.76, p.98-105
• Main Authors: Maione, Sabatino, Costa, Barbara, Piscitelli, Fabiana, Morera, Enrico, De Chiaro, Maria, Comelli, Francesca, Boccella, Serena, Guida, Francesca, Verde, Roberta, Ortar, Giorgio, Di Marzo, Vincenzo
• Format: Article
• Language: English
• Subjects: Amidohydrolases - antagonists & inhibitors; Analgesics - chemistry; Analgesics - therapeutic use; Anandamide; Animals; Arachidonic Acids - analysis; Arachidonic Acids - metabolism; Cannabinoid; Carbamates - chemistry; Carbamates - therapeutic use; Edema - drug therapy; Edema - enzymology; Edema - metabolism; Endocannabinoid; Endocannabinoids - analysis; Endocannabinoids - metabolism; FAAH; Male; Mice; Mice, Inbred C57BL; N-Arachidonoylserotonin; Pain - drug therapy; Pain - enzymology; Pain - metabolism; Pain Measurement - drug effects; Polyunsaturated Alkamides - analysis; Polyunsaturated Alkamides - metabolism; Transient Receptor Potential Channels - agonists; TRPA1; TRPA1 Cation Channel; TRPV Cation Channels - antagonists & inhibitors; TRPV1
• ISSN: 1043-6618; 1096-1186
• DOI: 10.1016/j.phrs.2013.07.003

We showed previously that inhibiting fatty acid amide hydrolase (FAAH), an endocannabinoid degrading 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-nociceptive and anti-hyperalgesic actions than the targeting of FAAH or TRPV1 alone. We also reported the synthesis of some piperazinyl carbamates as “dual” FAAH inhibitors and either antagonists at TRPV1 or agonists/desensitizers of the transient receptor potential ankyrin type-1 (TRPA1) cannel, another target for analgesic drugs. We investigated here if two such compounds, the FAAH/TRPV1 blocker OMDM198 and the FAAH inhibitor/TRPA1 agonist, OMDM202, exert anti-nociceptive actions in the formalin test of pain in mice, and through what mechanism. Both compounds inhibited the second phase of the response to formalin, the effect being maximal at 3mg/kg, i.p. Antagonism of CB1 or CB2 receptors with AM251 or AM630 (1mg/kg, i.p.), respectively, reversed this effect. A TRPV1 agonist, palvanil (0.1mg/kg, i.p.), also reversed the analgesic effect of OMDM198. OMDM202 action was also antagonized by a per se inactive dose of the selective TRPA1 blocker, AP-18 (0.05mg/kg, i.p.), but not by a TRPV1 antagonist. AP-18 at higher doses (0.1–0.2mg/kg) inhibited both the first and second phase of the formalin response. The effects of OMDM198 and OMDM202 were accompanied by elevation of anandamide levels in the spinal cord. OMDM198 (0.1–5.0mg/kg, i.p.) also reversed carrageenan-induced oedema and thermal hyperalgesia in mice with efficacy similar to that of AA-5-HT. These data suggest that “dual” fatty acid amide hydrolase and transient receptor potential channel modulators should be clinically evaluated as novel analgesics.