2014 Jul 12. pii: S0968-0896(14)00509-4. doi: 10.1016/j.bmc.2014.07.006. [Epub ahead of print]
Structure-affinity relationships and pharmacological characterization of new alkyl-resorcinol cannabinoidreceptor ligands: Identification of a dual cannabinoid receptor/TRPA1 channel agonist.
Brizzi A1, Aiello F2, Marini P3, Cascio MG4, Corelli F5, Brizzi V6, De Petrocellis L7, Ligresti A8, Luongo L9, Lamponi S6, Maione S9, Pertwee RG3, Di Marzo V8.
Abstract
In our ongoing program aimed at deeply investigating the endocannabinoid system (ES), a set of new alkyl-resorcinol derivatives was prepared focusing on the nature and the importance of the carboxamide functionality. Binding studies on CB1 and CB2 receptors, monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH) showed that some of the newly developed compounds behaved as very potent cannabinoid receptor ligands (Ki in the nanomolar range) while, however, none of them was able to inhibit MAGL and/or FAAH. Derivative 11 was a potent CB1 and CB2ligand, with Ki values similar to WIN 55,212, exhibiting a CB1 and CB2 agonist profile in vitro. In the formalin test of peripheral acute and inflammatory pain in mice, this compound showed a weak and delayed antinociceptive effect against the second phase of the nocifensive response, exhibiting, interestingly, a quite potent transient receptor potential ankyrin type-1 (TRPA1) channel agonist activity. Moreover, derivative 14, characterized by lower affinity but higher CB2 selectivity than 11, proved to behave as a weak CB2 competitive inverse agonist.
Copyright © 2014. Published by Elsevier Ltd.
Copyright © 2014. Published by Elsevier Ltd.
KEYWORDS:
Alkyl-resorcinol derivatives; Anandamide; Cannabinoid ligands; Endocannabinoids; Lipid modulators; Structure–affinity relationships; Transient receptor potential ankyrin type-1 channel
- PMID:
- 25065940
- [PubMed – as supplied by publisher]
