The discovery of a potent and selective pyrazolo-[2,3-e]-[1,2,4]-triazine cannabinoid type 2 receptor agonist

Moir Michael; Lane Samuel; Montgomery Andrew P.; Hibbs David; Connor Mark; Kassiou Michael

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The discovery of a potent and selective pyrazolo-[2,3-e]-[1,2,4]-triazine cannabinoid type 2 receptor agonist

机译：发现有效和选择性的吡唑-[2,3-e] - [1,2,4] - 三嗪类大麻素2型受体激动剂

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The development of selective CB2 receptor agonists is a promising therapeutic approach for the treatment of inflammatory diseases, without CB1 receptor mediated psychoactive side effects. Preliminary structure-activity relationship studies on pyrazoylidene benzamide agonists revealed the -ylidene benzamide moiety was crucial for functional activity at the CB2 receptor. A small library of compounds with varying linkage moieties between the pyrazole and substituted phenyl group has culminated in the discovery of a potent and selective pyrazolo-[2,3-e]-[1,2,4]-triazine agonist 19 (CB2R EC50 = 19 nM, CB1R EC50 > 10 mu M). Docking studies have revealed key structural features of the linkage group that are important for potent functional activity. (C) 2020 Elsevier Masson SAS. All rights reserved.

机译：选择性CB2受体激动剂的开发是治疗炎症性疾病的一种有希望的治疗方法，没有CB1受体介导的精神活性副作用。对吡唑亚基苯甲酰胺激动剂的初步构效关系研究表明，-亚基苯甲酰胺部分对CB2受体的功能活性至关重要。一个在吡唑和取代苯基之间具有不同连接部分的小化合物库最终发现了一种有效且选择性的吡唑-[2,3-e]-[1,2,4]-三嗪激动剂19（CB2R EC50=19 nM，CB1R EC50>10μM）。对接研究揭示了连锁群的关键结构特征，这些特征对有效的功能活动非常重要。（C） 2020年爱思唯尔马森SAS。版权所有。

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《European Journal of Medicinal Chemistry: Chimie Therapeutique》 |2021年第1期|共28页
作者
Moir Michael; Lane Samuel; Montgomery Andrew P.; Hibbs David; Connor Mark; Kassiou Michael;
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作者单位

Univ Sydney Sch Chem Sydney NSW 2006 Australia;

Univ Sydney Fac Hlth Sci Sydney NSW 2006 Australia;

Univ Sydney Sch Chem Sydney NSW 2006 Australia;

Univ Sydney Sydney Pharm Sch Sydney NSW 2006 Australia;

Macquarie Univ Dept Biomed Sci Sydney NSW 2109 Australia;

Univ Sydney Sch Chem Sydney NSW 2006 Australia;

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正文语种 eng
中图分类药学;
关键词
Cannabinoid; Synthesis; Pyrazolotriazine; Docking; Structure-activity relationship study; CB2R selective;

机译：大麻素;合成吡唑三嗪;对接;构效关系研究;CB2R选择性;

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The discovery of a potent and selective pyrazolo-[2,3-e]-[1,2,4]-triazine cannabinoid type 2 receptor agonist

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