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Modulating β-arrestin 2 recruitment at the δ- and μ-opioid receptors using peptidomimetic ligands
RSC Medicinal Chemistry ( IF 4.1 ) Pub Date : 2021-08-16 , DOI: 10.1039/d1md00025j Krishna K Sharma 1 , Robert J Cassell 2 , Yazan J Meqbil 2, 3 , Hongyu Su 2 , Arryn T Blaine 2, 4 , Benjamin R Cummins 5 , Kendall L Mores 2 , David K Johnson 6 , Richard M van Rijn 2, 7, 8 , Ryan A Altman 2, 5
RSC Medicinal Chemistry ( IF 4.1 ) Pub Date : 2021-08-16 , DOI: 10.1039/d1md00025j Krishna K Sharma 1 , Robert J Cassell 2 , Yazan J Meqbil 2, 3 , Hongyu Su 2 , Arryn T Blaine 2, 4 , Benjamin R Cummins 5 , Kendall L Mores 2 , David K Johnson 6 , Richard M van Rijn 2, 7, 8 , Ryan A Altman 2, 5
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μ-Opioid receptor agonists provide potent and effective acute analgesia; however, their therapeutic window narrows considerably upon repeated administration, such as required for treating chronic pain. In contrast, bifunctional μ/δ opioid agonists, such as the endogenous enkephalins, have potential for treating both acute and chronic pain. However, enkephalins recruit β-arrestins, which correlate with certain adverse effects at μ- and δ-opioid receptors. Herein, we identify the C-terminus of Tyr-ψ[(Z)CF![[double bond, length as m-dash]](https://www.rsc.org/images/entities/char_e001.gif)
CH]-Gly-Leu-enkephalin, a stable enkephalin derivative, as a key site to regulate bias of both δ- and μ-opioid receptors. Using in vitro assays, substitution of the Leu5 carboxylate with amides (NHEt, NMe2, NCyPr) reduced β-arrestin recruitment efficacy through both the δ-opioid and μ-opioid, while retaining affinity and cAMP potency. For this series, computational studies suggest key ligand–receptor interactions that might influence bias. These findings should enable the discovery of a range of tool compounds with previously unexplored biased μ/δ opioid agonist pharmacological profiles.
中文翻译：
使用拟肽配体调节 δ- 和 μ- 阿片受体上的 β-arrestin 2 募集
μ-阿片受体激动剂提供强效和有效的急性镇痛；然而，它们的治疗窗口在重复给药后会大大缩小，例如治疗慢性疼痛所需的。相比之下，双功能 μ/δ 阿片样物质激动剂，例如内源性脑啡肽，具有治疗急性和慢性疼痛的潜力。然而，脑啡肽会招募 β-抑制素，这与对 μ-和 δ-阿片受体的某些不良反应相关。在此，我们确定了 Tyr-ψ[( Z )CFCH]-Gly-Leu-脑啡肽（一种稳定的脑啡肽衍生物）的 C 端，作为调节 δ-和 μ-阿片受体偏向的关键位点。使用体外测定，用酰胺（NHEt、NMe 2 、 NCy Pr) 通过 δ-阿片类药物和 μ-阿片类药物降低 β-arrestin 募集功效，同时保持亲和力和 cAMP 效力。对于本系列，计算研究表明可能影响偏差的关键配体-受体相互作用。这些发现应该能够发现一系列具有以前未探索的偏倚 μ/δ 阿片样物质激动剂药理学特征的工具化合物。
更新日期：2021-09-08
CH]-Gly-Leu-enkephalin, a stable enkephalin derivative, as a key site to regulate bias of both δ- and μ-opioid receptors. Using in vitro assays, substitution of the Leu5 carboxylate with amides (NHEt, NMe2, NCyPr) reduced β-arrestin recruitment efficacy through both the δ-opioid and μ-opioid, while retaining affinity and cAMP potency. For this series, computational studies suggest key ligand–receptor interactions that might influence bias. These findings should enable the discovery of a range of tool compounds with previously unexplored biased μ/δ opioid agonist pharmacological profiles.
中文翻译：
使用拟肽配体调节 δ- 和 μ- 阿片受体上的 β-arrestin 2 募集
μ-阿片受体激动剂提供强效和有效的急性镇痛；然而，它们的治疗窗口在重复给药后会大大缩小，例如治疗慢性疼痛所需的。相比之下，双功能 μ/δ 阿片样物质激动剂，例如内源性脑啡肽，具有治疗急性和慢性疼痛的潜力。然而，脑啡肽会招募 β-抑制素，这与对 μ-和 δ-阿片受体的某些不良反应相关。在此，我们确定了 Tyr-ψ[( Z )CF
CH]-Gly-Leu-脑啡肽（一种稳定的脑啡肽衍生物）的 C 端，作为调节 δ-和 μ-阿片受体偏向的关键位点。使用体外测定，用酰胺（NHEt、NMe 2 、 NCy Pr) 通过 δ-阿片类药物和 μ-阿片类药物降低 β-arrestin 募集功效，同时保持亲和力和 cAMP 效力。对于本系列，计算研究表明可能影响偏差的关键配体-受体相互作用。这些发现应该能够发现一系列具有以前未探索的偏倚 μ/δ 阿片样物质激动剂药理学特征的工具化合物。
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