title: Piperazinyl carbamate fatty acid amide hydrolase inhibitors and transient receptor potential channel modulators as "dual-target" analgesics.
abstract: 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 3 mg/kg, i.p. Antagonism of CB1 or CB2 receptors with AM251 or AM630 (1 mg/kg, i.p.), respectively, reversed this effect. A TRPV1 agonist, palvanil (0.1 mg/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 (0.05 mg/kg, i.p.), but not by a TRPV1 antagonist. AP-18 at higher doses (0.1-0.2 mg/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 (0.1-5.0 mg/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.
authors.affiliation: Endocannabinoid Research Group, Department of Experimental Medicine - Division of Pharmacology 'L. Donatelli', Second University of Naples, Naples, Italy.
authors.forename: Sabatino
authors.initials: S
authors.lastname: Maione
authors.forename: Barbara
authors.initials: B
authors.lastname: Costa
authors.forename: Fabiana
authors.initials: F
authors.lastname: Piscitelli
authors.forename: Enrico
authors.initials: E
authors.lastname: Morera
authors.forename: Maria
authors.initials: M
authors.lastname: De Chiaro
authors.forename: Francesca
authors.initials: F
authors.lastname: Comelli
authors.forename: Serena
authors.initials: S
authors.lastname: Boccella
authors.forename: Francesca
authors.initials: F
authors.lastname: Guida
authors.forename: Roberta
authors.initials: R
authors.lastname: Verde
authors.forename: Giorgio
authors.initials: G
authors.lastname: Ortar
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Di Marzo
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors*; D000700:Analgesics / Q000737:chemistry / Q000627:therapeutic use*; D000818:Animals; D001095:Arachidonic Acids / Q000032:analysis / Q000378:metabolism; D002219:Carbamates / Q000737:chemistry / Q000627:therapeutic use*; D004487:Edema / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism; D063388:Endocannabinoids / Q000032:analysis / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010146:Pain / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D010147:Pain Measurement / Q000187:drug effects; D053284:Polyunsaturated Alkamides / Q000032:analysis / Q000378:metabolism; D000074025:TRPA1 Cation Channel; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors; D050051:Transient Receptor Potential Channels / Q000819:agonists; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D000700:Analgesics; D001095:Arachidonic Acids; D002219:Carbamates; D063388:Endocannabinoids; D053284:Polyunsaturated Alkamides; D000074025:TRPA1 Cation Channel; D050916:TRPV Cation Channels; D050051:Transient Receptor Potential Channels; D000099252:Fatty Acid Amide Hydrolases; C000604341:OMDM-198; C494484:TRPV1 receptor; C475685:Trpa1 protein, mouse; C078814:anandamide
keywords: Anandamide; Cannabinoid; Endocannabinoid; FAAH; N-Arachidonoylserotonin; TRPA1; TRPV1