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

被引：14

作者：

Brizzi, Antonella ^{[1
]}

Aiello, Francesca ^{[2
]}

Marini, Pietro ^{[3
]}

Cascio, Maria Grazia ^{[3
,4
]}

Corelli, Federico ^{[1
]}

Brizzi, Vittorio ^{[1
]}

De Petrocellis, Luciano ^{[5
]}

Ligresti, Alessia ^{[4
]}

Luongo, Livio ^{[6
]}

Lamponi, Stefania ^{[1
]}

Maione, Sabatino ^{[6
]}

Pertwee, Roger G. ^{[3
]}

Di Marzo, Vincenzo ^{[4
]}

机构：

[1] Univ Siena, Dipartimento Biotecnol Chim & Farm, I-53100 Siena, Italy

[2] Univ Calabria, Dipartimento Farm & Sci Salute & Nutr, I-87036 Cosenza, Italy

[3] Univ Aberdeen, Inst Med Sci, Aberdeen, Scotland

[4] CNR, Ist Chim Biomol, Endocannabinoid Res Grp, I-80078 Naples, Italy

[5] CNR, Ist Cibernet, Endocannabinoid Res Grp, I-80078 Naples, Italy

[6] Univ Naples 2, Sez Farmacol L Donatelli, Dipartimento Med Sperimentale, I-80138 Naples, Italy

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2014年 / 22卷 / 17期

关键词：

Cannabinoid ligands; Transient receptor potential ankyrin type-1 channel; Structure-affinity relationships; Alkyl-resorcinol derivatives; Anandamide; Endocannabinoids; Lipid modulators; NUCLEAR-MAGNETIC-RESONANCE; ARACHIDONYLETHANOLAMIDE ANANDAMIDE; MOLECULAR CHARACTERIZATION; POTENT LIGANDS; NOLADIN ETHER; CB1; BINDING; ENZYME; ENDOCANNABINOIDS; REQUIREMENTS;

D O I：

10.1016/j.bmc.2014.07.006

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

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 (K-i 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 K-i 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. (C) 2014 Elsevier Ltd. All rights reserved.

引用

页码：4770 / 4783

页数：14

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