Polypharmacological profile of 1,2-dihydro-2-oxo-pyridine-3-carboxamides in the endocannabinoid system
Polypharmacological profile of 1,2-dihydro-2-oxo-pyridine-3-carboxamides in the endocannabinoid system
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DOI：
10.1016/j.ejmech.2018.05.019
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发表时间：
2018-06-25
影响因子：
6.7
通讯作者：
Manera, Clementina
中科院分区：
文献类型：
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作者：
Chicca, Andrea;Arena, Chiara;Manera, Clementina
内源性大麻素系统（ECS）代表参与不同生理和病理过程的主要神经调节系统之一。多靶点化合物通过多种作用机制发挥其活性，代表了 ECS 的一种有前途的药理学调节。在这项工作中，我们报告了 4-取代和 4,5-二取代 1,2-二氢-2-氧代-吡啶-3-甲酰胺衍生物，对大麻素受体具有广谱的亲和力和功能活性，并对 ECS 主要成分产生额外影响。特别是，化合物 B3 对 CB1R（K-i = 23.1 nM，部分激动剂）和 CB2R（K-i = 6.9 nM，反向激动剂）表现出高亲和力，并且对 FAAH 具有显着的抑制活性（IC50 = 70 nM），对 ABHD12 具有中度抑制作用（IC50 = 2.5 μM）。化合物 B4、B5 和 B6 充当 CB1R 的完全激动剂和 CB2R 的部分激动剂（B5 和 B6）或拮抗剂（B4），通过以亚微摩尔 IC50 值（0.28-0.62 μM）抑制 anandamide 摄取，表现出额外的多靶点特性。最好的衍生物对 U937 类淋巴母细胞表现出细胞毒活性。最后，对CB1R和CB2R以及FAAH的三维结构进行分子对接分析，合理化了该系列化合物的构效关系。 (C) 2018 Elsevier Masson SAS。版权所有。
The endocannabinoid system (ECS) represents one of the major neuromodulatory systems involved in different physiological and pathological processes. Multi-target compounds exert their activities by acting via multiple mechanisms of action and represent a promising pharmacological modulation of the ECS. In this work we report 4-substituted and 4,5-disubstituted 1,2-dihydro-2-oxo-pyridine-3-carboxamide derivatives with a broad spectrum of affinity and functional activity towards both cannabinoid receptors and additional effects on the main components of the ECS. In particular compound B3 showed high affinity for CB1R (K-i = 23.1 nM, partial agonist) and CB2R (K-i = 6.9 nM, inverse agonist) and also significant inhibitory activity (IC50 = 70 nM) on FAAH with moderate inhibition of ABHD12 (IC50 = 2.5 mu M). Compounds B4, B5 and B6 that act as full agonists at CB1R and as partial agonists (B5 and B6) or antagonist (B4) at CB2R, exhibited an additional multi-target property by inhibiting anandamide uptake with sub-micromolar IC50 values (0.28-0.62 mu M). The best derivatives showed cytotoxic activity on U937 lymphoblastoid cells. Finally, molecular docking analysis carried out on the three-dimensional structures of CB1R and CB2R and of FAAH allowed to rationalize the structure-activity relationships of this series of compounds. (C) 2018 Elsevier Masson SAS. All rights reserved.