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: Sabatino Maione, Barbara Costa, Fabiana Piscitelli, Enrico Morera, Maria De Chiaro, Francesca Comelli, Serena Boccella, Francesca Guida, Roberta Verde, Giorgio Ortar, Vincenzo Di Marzo
• Journal: Pharmacological research (Pharmacol Res) Vol. 76 Pg. 98-105 (Oct 2013) ISSN: 1096-1186 [Electronic] Netherlands
• PMID: 23911581 (Publication Type: Journal Article)
• Copyright: Copyright © 2013 Elsevier Ltd. All rights reserved.

Chemical References

• Analgesics
• Arachidonic Acids
• Carbamates
• Endocannabinoids
• OMDM-198
• Polyunsaturated Alkamides
• TRPA1 Cation Channel
• TRPV Cation Channels
• TRPV1 receptor
• Transient Receptor Potential Channels
• Trpa1 protein, mouse
• Amidohydrolases
• fatty-acid amide hydrolase
• anandamide

Topics

• Amidohydrolases (antagonists & inhibitors)
• Analgesics (chemistry, therapeutic use)
• Animals
• Arachidonic Acids (analysis, metabolism)
• Carbamates (chemistry, therapeutic use)
• Edema (drug therapy, enzymology, metabolism)
• Endocannabinoids (analysis, metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Pain (drug therapy, enzymology, metabolism)
• Pain Measurement (drug effects)
• Polyunsaturated Alkamides (analysis, metabolism)
• TRPA1 Cation Channel
• TRPV Cation Channels (antagonists & inhibitors)
• Transient Receptor Potential Channels (agonists)