Novel analogs of PSNCBAM-1 as allosteric modulators of cannabinoid CB1 receptor

被引：14

作者：

Bertini, Simone ^{[1
]}

Chicca, Andrea ^{[2
]}

Gado, Francesca ^{[1
]}

Arena, Chiara ^{[1
]}

Nieri, Daniela ^{[2
]}

Digiacomo, Maria ^{[1
]}

Saccomanni, Giuseppe ^{[1
]}

Zhao, Pingwei ^{[3
]}

Abood, Mary E. ^{[3
]}

Macchia, Marco ^{[1
]}

Gertsch, Jurg ^{[2
]}

Manera, Clementina ^{[1
]}

机构：

[1] Univ Pisa, Dept Pharm, I-56126 Pisa, Italy

[2] Univ Bern, NCCR TransCure, Inst Biochem & Mol Med, Buhlstr 28, CH-3012 Bern, Switzerland

[3] Temple Univ, Lewis Katz Sch Med, Ctr Subst Abuse Res, Philadelphia, PA 19140 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2017年 / 25卷 / 24期

关键词：

Allosteric modulator; CB1; receptor; Endocannabinoid system; MAPK/ERK signaling pathway; Serum response element; ENDOCANNABINOID SYSTEM; HUMAN HEALTH; PHARMACOLOGY; STRATEGIES; AGONISTS; PAIN;

D O I：

10.1016/j.bmc.2017.10.015

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

In this work, we explored the molecular framework of the known CB1R allosteric modulator PSNCBAM-1 with the aim to generate new bioactive analogs and to deepen the structure-activity relationships of this type of compounds. In particular, the introduction of a NH group between the pyridine ring and the phenyl nucleus generated the amino-phenyl-urea derivative SN15b that behaved as a positive allosteric modulator (PAM), increasing the CB1R binding affinity of the orthosteric ligand CP55,940. The functional activity was evaluated using serum response element (SRE) assay, which assesses the CB1R-dependent activation of the MAPK/ERK signaling pathway. SN15b and the biphenyl-urea analog SC4a significantly inhibited the response produced by CP55,940 in the low mu M range, thus behaving as negative allosteric modulators (NAMs). The new derivatives presented here provide further insights about the modulation of CB1R binding and functional activity by allosteric ligands. (C) 2017 Elsevier Ltd. All rights reserved.

引用

页码：6427 / 6434

页数：8

共 46 条

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