Novel Diarylurea Based Allosteric Modulators of the Cannabinoid CB1 Receptor: Evaluation of Importance of 6-Pyrrolidinylpyridinyl Substitution

被引：21

作者：

Nguyen, Thuy ^{[1
]}

German, Nadezhda ^{[1
]}

Decker, Ann M. ^{[1
]}

Langston, Tiffany L. ^{[1
]}

Gamage, Thomas F. ^{[1
]}

Farquhar, Charlotte E. ^{[1
]}

Li, Jun-Xu ^{[2
]}

Wiley, Jenny L. ^{[1
]}

Thomas, Brian F. ^{[1
]}

Zhang, Yanan ^{[1
]}

机构：

[1] Res Triangle Inst, Res Triangle Pk, NC 27709 USA

[2] Univ Buffalo State Univ New York, Dept Pharmacol & Toxicol, Buffalo, NY 14214 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2017年 / 60卷 / 17期

基金：

中国国家自然科学基金; 美国国家卫生研究院;

关键词：

ANTAGONIST; COCAINE; RELAPSE; REINSTATEMENT; MECHANISM; FLUORINE; SEEKING;

D O I：

10.1021/acs.jmedchem.7b00707

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Allosteric modulators of the cannabinoid CB1 receptor have recently been reported as an alternative approach to modulate the CB1 receptor for therapeutic benefits. In this study, we report the design and synthesis of a series of diarylureas derived from PSNCBAM-1 (2). Similar to 2, these diarylureas dose-dependently inhibited CPSS,940-induced intracellular calcium mobilization and [S-35]GTP-gamma-S binding while enhancing [H-3]CPSS,940 binding to the CB1 receptor. Structure activity relationship studies revealed that the pyridinyl ring of 2 could be replaced by other aromatic rings and the pyrrolidinyl ring is not required for CB1 allosteric modulation. 34 (RTICBM-74) had similar potencies as 2 in all in vitro assays but showed significantly improved metabolic stability to rat liver microsomes. More importantly, 34 was, more effective than 2 in attenuating the reinstatement of extinguished cocaine-seeking behavior in rats, demonstrating the potential of this diarylurea series as promising candidates for the development of relapse treatment of cocaine addiction.

引用

页码：7410 / 7424

页数：15

共 31 条

[1] CB1 Receptor Allosteric Modulators Display Both Agonist and Signaling Pathway Specificity [J].