ML417的发现，优化和表征：新型且高度选择性的D3多巴胺受体激动剂。,Journal of Medicinal Chemistry

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ML417的发现，优化和表征：新型且高度选择性的D3多巴胺受体激动剂。
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-04-28 , DOI: 10.1021/acs.jmedchem.0c00424
Amy E Moritz ₁ , R Benjamin Free ₁ , Warren S Weiner ₂ , Emmanuel O Akano ₁ , Disha Gandhi ₃ , Ara Abramyan ₄ , Thomas M Keck ₅ , Marc Ferrer ₆ , Xin Hu ₆ , Noel Southall ₆ , Joseph Steiner ₇ , Jeffrey Aubé _{2,

3} , Lei Shi ₄ , Kevin J Frankowski _{2,

3} , David R Sibley ₁

Affiliation

Molecular Neuropharmacology Section, National Institute of Neurological Disorders and Stroke, Intramural Research Program, National Institutes of Health, 35 Convent Drive, MSC-3723, Bethesda, Maryland 20892-3723, United States.
University of Kansas Specialized Chemistry Center, University of Kansas, Lawrence, Kansas 66047, United States.
Center for Integrative Chemical Biology and Drug Discovery, UNC Eshelman School of Pharmacy, 125 Mason Farm Road, Chapel Hill, North Carolina 27599, United States.
Computational Chemistry and Molecular Biophysics Unit, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, Maryland, 333 Cassell Drive, Baltimore, Maryland 21224, United States.
Department of Chemistry & Biochemistry, Department of Molecular & Cellular Biosciences, College of Science and Mathematics, Rowan University, 201 Mullica Hill Road, Glassboro, New Jersey 08028, United States.
NIH Chemical Genomics Center, Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland 20850, United States.
NeuroTherapeutics Development Unit, National Institute for Neurological Disorders and Stroke, Intramural Research Program, National Institutes of Health, Bethesda, Maryland 20892, United States.

为了鉴定新型D3多巴胺受体（D3R）激动剂，我们使用β-arrestin募集试验进行了高通量筛选。对命中化合物的反筛选提供了对其选择性，功效和效能的评估。最有前途的支架通过药物化学进行了优化，从而提高了效能和选择性。优化的化合物ML417（20）可有效促进D3R介导的β-arrestin移位，G蛋白活化和ERK1 / 2磷酸化（pERK），同时对其他多巴胺受体缺乏活性。针对多种G蛋白偶联受体的ML417筛选显示出卓越的整体选择性。分子建模表明ML417以独特的方式与D3R相互作用，可能解释了其非凡的选择性。还发现ML417可以防止源自iPSC的多巴胺能神经元的神经变性。结合有希望的药代动力学和毒理学特征，这些结果表明ML417是一种新颖且独特的选择性D3R激动剂，可作为治疗神经精神疾病的研究工具和治疗先导。

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更新日期：2020-04-28

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