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Structure-affinity relationships and pharmacological characterization of new alkyl-resorcinol cannabinoid receptor ligands: Identification of a dual cannabinoid receptor/TRPA1 channel agonist.

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 CB2 ligand, 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.

journal_name

Bioorg Med Chem

journal_title

Bioorganic & medicinal chemistry

authors

Brizzi A,Aiello F,Marini P,Cascio MG,Corelli F,Brizzi V,De Petrocellis L,Ligresti A,Luongo L,Lamponi S,Maione S,Pertwee RG,Di Marzo V

doi

10.1016/j.bmc.2014.07.006

subject

Has Abstract

pub_date

2014-09-01 00:00:00

pages

4770-83

issue

17

eissn

0968-0896

issn

1464-3391

pii

S0968-0896(14)00509-4

journal_volume

22

pub_type

杂志文章

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