Synthesis, biological activity and molecular modeling of new biphenylic carboxamides as potent and selective CB2 receptor ligands

被引：18

作者：

Bertini, Simone ^{[1
]}

Parkkari, Teija ^{[2
,3
]}

Savinainen, Juha R. ^{[3
]}

Arena, Chiara ^{[1
]}

Saccomanni, Giuseppe ^{[1
]}

Saguto, Simone ^{[1
]}

Ligresti, Alessia ^{[4
]}

Allara, Marco ^{[4
]}

Bruno, Agostino ^{[5
]}

Marinelli, Luciana ^{[5
]}

Di Marzo, Vincenzo ^{[4
]}

Novellino, Ettore ^{[5
]}

Manera, Clementina ^{[1
]}

Macchia, Marco ^{[1
]}

机构：

[1] Univ Pisa, Dipartimento Farm, I-56126 Pisa, Italy

[2] Univ Eastern Finland, Sch Pharm, Fac Hlth Sci, FL-70211 Kuopio, Finland

[3] Univ Eastern Finland, Inst Biomed, Sch Med, Fac Hlth Sci, FL-70211 Kuopio, Finland

[4] CNR, Ist Chim Biomol, Endocannabinoid Res Grp, I-80125 Naples, Italy

[5] Univ Napoli Federico II, Dipartimento Farm, I-80131 Naples, Italy

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2015年 / 90卷

基金：

芬兰科学院;

关键词：

Cannabinoid; CB2; receptor; CB2 receptor neutral antagonist; Biphenylic carboxamides; CANNABINOID RECEPTOR; ENDOCANNABINOID SYSTEM; INVERSE AGONISTS; IN-VITRO; ANTAGONIST; BINDING; IDENTIFICATION; STRATEGIES; DISCOVERY; TARGET;

D O I：

10.1016/j.ejmech.2014.11.066

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The CB2 receptor is a therapeutic target of increasing importance for several diseases, including pain, inflammation, neurodegeneration, cancer and osteoporosis. While several compounds showing CB2-selective agonist or inverse agonist properties have been developed, only few CB2 receptor selective neutral antagonists are actually known. Such type of compounds could be useful to study more in depth the role of the CB2 receptor, because they lack the ability to counteract its "constitutive" activity. Here we describe the synthesis and biological activity of a series of biphenylic carboxamides as a new class of CB2 receptor selective ligands. In binding assays, one of these compounds showed good CB2 receptor affinity and selectivity (K-i = 11.48 nM; Selectivity Index = 130). Furthermore, in functional assays, the same compound showed a very interesting pharmacological profile as CB2 receptor selective neutral antagonist. These results pave the way to further developments, including structural optimization, with the aim to obtain more potent CB2 receptor ligands with this peculiar feature. (C) 2014 Elsevier Masson SAS. All rights reserved.

引用

页码：526 / 536

页数：11

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[1] Targeting CB2 receptors and the endocannabinoid system for the treatment of pain [J].