Piperazinyl carbamate fatty acid amide hydrolase inhibitors and transient receptor potential channel modulators as ¡°dual-target¡± analgesics
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- 作者：Sabatino Maione ; Barbara Costa ; Fabiana Piscitelli ; Enrico Morera ; Maria De Chiaro ; Francesca Comelli ; Serena Boccella ; Francesca Guida ; Roberta Verde ; Giorgio Ortar ; Vincenzo Di Marzo
- 关键词：Cannabinoid ; Endocannabinoid ; Anandamide ; FAAH ; TRPV1 ; TRPA1 ; N-Arachidonoylserotonin
- 刊名：Pharmacological Research
- 出版年：2013
- 出版时间：October, 2013
- 年：2013
- 卷：76
- 期：Complete
- 页码：98-105
- 全文大小：1524 K
文摘
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.