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首页> 外文期刊>European Journal of Medicinal Chemistry: Chimie Therapeutique >(2S)-N-2-methoxy-2-phenylethyl-6,7-benzomorphan compound (2S-LP2): Discovery of a biased mu/delta opioid receptor agonist
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(2S)-N-2-methoxy-2-phenylethyl-6,7-benzomorphan compound (2S-LP2): Discovery of a biased mu/delta opioid receptor agonist

机译：（2S）-N-2-甲氧基-2-苯基乙基-6,7-苯并甲烷化合物（2S-LP2）：发现偏差MU / DELTA阿片受体激动剂

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摘要

The pivotal role of the stereocenter at the N-substituent of the 6,7-benzomorphan scaffold was investigated combining synthetic and pharmacological approaches. 2R- and 2S-diastereoisomers of the multitarget MOR/DOR antinociceptive ligand LP2 (1) were synthesized and their pharmacological profile was evaluated in in vitro and vivo assays. From our results, 2S-LP2 (5) showed an improved pharmacological profile in comparison to LP2 (1) and 2R-LP2 (4). 2S-LP2 (5) elicited an antinociceptive effect with a 1.5- and 3-times higher potency than LP2 (I) and R-antipode (4), respectively. In vivo effect of 2S-LP2 (5) was consistent with the improved MOR/DOR efficacy profile assessed by radioligand binding assay, to evaluate the opioid receptor affinity, and BRET assay, to evaluate the capability to promote receptor/G-protein and receptor/beta-arrestin 2 interaction. 2S-LP2 (5) was able to activate, with different efficacy, G-protein pathway over beta-arrestin 2, behaving as biased agonist at MOR and mainly at DOR Considering the therapeutic potential of both multitarget MOR/DOR agonism and functional selectivity over G-protein, the 2S-LP2 (5) biased multitarget MOR/DOR agonist could provide a safer treatment opportunity. (C) 2019 Elsevier Masson SAS. All rights reserved.
机译：研究了合成和药理学方法的6,7-苯甲酰胺支架的N-取代基在6,7-苯并鼠支架的枢轴作用。合成了多元组织MOR / DOR抗血型双层配体LP2（1）的2R-和2S-非映异构体，并在体外和体内测定中评估其药理学曲线。从我们的结果，与LP2（1）和2R-LP2（4）相比，2S-LP2（5）显示了改善的药理学分布。 2S-LP2（5）分别引发了比LP2（I）和R-Antipode（4）的1.5-和3倍效力的抗血质效果。 2S-LP2（5）的体内效果与通过放射性配体结合测定评估的改进的MOR / DOR功效曲线一致，以评估阿片受体亲和力和BRET测定，评价促进受体/ G蛋白和受体的能力/ beta-arrestin 2互动。 2S-LP2（5）能够以不同的疗效激活，β-inscrectin 2的不同疗效，表现为MOR的偏向激动剂，主要在DOR考虑多靶莫/ DOR激动激动和功能选择性G-蛋白，2S-LP2（5）偏置多价MOR / DOR激动剂可以提供更安全的处理机会。 （c）2019年Elsevier Masson SAS。版权所有。

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