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Discovery and Structure-Activity Relationships of Nociceptin Receptor Partial Agonists That Afford Symptom Ablation in Parkinson's Disease Models.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-02-03 , DOI: 10.1021/acs.jmedchem.9b02134 Uma Gayathri Kamakolanu 1 , Michael E Meyer 1 , Dennis Yasuda 1 , Willma E Polgar 1 , Matteo Marti 2 , Daniela Mercatelli 3 , Clarissa Anna Pisanò 3 , Alberto Brugnoli 3 , Michele Morari 3 , Nurulain T Zaveri 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-02-03 , DOI: 10.1021/acs.jmedchem.9b02134 Uma Gayathri Kamakolanu 1 , Michael E Meyer 1 , Dennis Yasuda 1 , Willma E Polgar 1 , Matteo Marti 2 , Daniela Mercatelli 3 , Clarissa Anna Pisanò 3 , Alberto Brugnoli 3 , Michele Morari 3 , Nurulain T Zaveri 1
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A novel series of C(3)-substituted piperdinylindoles were developed as nociceptin opioid receptor (NOP) partial agonists to explore a pharmacological hypothesis that NOP partial agonists would afford a dual pharmacological action of attenuating Parkinson's disease (PD) motor symptoms and development of levodopa-induced dyskinesias. SAR around the C-3 substituents investigated effects on NOP binding, intrinsic activity, and selectivity and showed that while the C(3)-substituted indoles are selective, high affinity NOP ligands, the steric, polar, and cationic nature of the C-3 substituents affected intrinsic activity to afford partial agonists with a range of efficacies. Compounds 4, 5, and 9 with agonist efficacies between 25% and 35% significantly attenuated motor deficits in the 6-OHDA-hemilesioned rat model of PD. Further, unlike NOP antagonists, which appear to worsen dyskinesia expression, these NOP partial agonists did not attenuate or worsen dyskinesia expression. The NOP partial agonists and their SAR reported here may be useful to develop nondopaminergic treatments for PD.
中文翻译：
在帕金森氏病模型中出现症状消融的痛觉肽受体局部激动剂的发现与构效关系。
开发了一系列新型的C（3）取代的哌啶基吲哚作为伤害感受肽阿片受体（NOP）部分激动剂，以探索药理学假设，即NOP部分激动剂将提供双重药理作用，以减轻帕金森氏病（PD）的运动症状和左旋多巴的发展引起的运动障碍。围绕C-3取代基的SAR研究了对NOP结合，内在活性和选择性的影响，并表明尽管C（3）取代的吲哚是选择性的，高亲和力的NOP配体，但C-的空间，极性和阳离子性质3个取代基影响内在活性，从而提供具有一定功效的部分激动剂。激动剂效率在25％到35％之间的化合物4、5和9在6-OHDA肥胖大鼠PD模型中显着减轻了运动功能障碍。进一步，与NOP拮抗剂似乎会加剧运动障碍的表达不同，这些NOP部分激动剂不会减弱或加剧运动障碍的表达。此处报道的NOP部分激动剂及其SAR可能有助于开发PD的非多巴胺能治疗。
更新日期：2020-02-03
中文翻译：
在帕金森氏病模型中出现症状消融的痛觉肽受体局部激动剂的发现与构效关系。
开发了一系列新型的C（3）取代的哌啶基吲哚作为伤害感受肽阿片受体（NOP）部分激动剂，以探索药理学假设，即NOP部分激动剂将提供双重药理作用，以减轻帕金森氏病（PD）的运动症状和左旋多巴的发展引起的运动障碍。围绕C-3取代基的SAR研究了对NOP结合，内在活性和选择性的影响，并表明尽管C（3）取代的吲哚是选择性的，高亲和力的NOP配体，但C-的空间，极性和阳离子性质3个取代基影响内在活性，从而提供具有一定功效的部分激动剂。激动剂效率在25％到35％之间的化合物4、5和9在6-OHDA肥胖大鼠PD模型中显着减轻了运动功能障碍。进一步，与NOP拮抗剂似乎会加剧运动障碍的表达不同，这些NOP部分激动剂不会减弱或加剧运动障碍的表达。此处报道的NOP部分激动剂及其SAR可能有助于开发PD的非多巴胺能治疗。
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