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同时靶向 D 型受体和 5-羟色胺受体的 1,4-二氧六环化合物：有望用于治疗帕金森病或精神分裂症

Multitarget 1,4-Dioxane Compounds Combining Favorable D-like and 5-HT Receptor Interactions with Potential for the Treatment of Parkinson's Disease or Schizophrenia.

机构信息

Scuola di Scienze del Farmaco e dei Prodotti della Salute , Università di Camerino , Via S. Agostino 1 , 62032 Camerino , Italy.

Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch , National Institute on Drug Abuse - Intramural Research Program, National Institutes of Health , 333 Cassell Drive , Baltimore , Maryland 21224 , United States.

出版信息

ACS Chem Neurosci. 2019 May 15;10(5):2222-2228. doi: 10.1021/acschemneuro.8b00677. Epub 2019 Jan 9.

DOI:10.1021/acschemneuro.8b00677
PMID:30609891
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8378419/
Abstract

The effect of methoxy and hydroxy substitutions in different positions of the phenoxy moiety of the N-((6,6-diphenyl-1,4-dioxan-2-yl)methyl)-2-phenoxyethan-1-amine scaffold on the affinity/activity for D-like, 5-HT, and α-adrenoceptor subtypes was evaluated. Multitarget compounds with suitable combinations of dopaminergic and serotoninergic profiles were discovered. In particular, the 2-methoxy derivative 3 showed a multitarget combination of 5-HT/D agonism and D/D/5-HT antagonism, which may be a favorable profile for the treatment of schizophrenia. Interestingly, the 3-hydroxy derivative 8 behaved as a partial agonist at D and as a potent full agonist at D and D subtypes. In addition to its potent 5-HT receptor agonism, such a dopaminergic profile makes 8 a potential multitarget compound for the treatment of Parkinson's disease (PD). Indeed, the activation of 5-HT receptors might be helpful in reducing dyskinetic side effects associated with dopaminergic stimulation.

摘要

评估了 N-((6,6-二苯基-1,4-二恶烷-2-基)甲基)-2-苯氧基乙胺支架中苯氧基部分的不同位置的甲氧基和羟基取代对 D 样、5-HT 和 α-肾上腺素能受体亚型的亲和力/活性的影响。发现了具有合适多巴胺能和血清素能特征组合的多靶化合物。特别是，2-甲氧基衍生物 3 表现出 5-HT/D 激动作用和 D/D/5-HT 拮抗作用的多靶组合，这可能是治疗精神分裂症的有利特征。有趣的是，3-羟基衍生物 8 作为 D 部分的部分激动剂，作为 D 和 D 亚型的有效完全激动剂。除了其有效的 5-HT 受体激动作用外，这种多巴胺能特征使 8 成为治疗帕金森病（PD）的潜在多靶化合物。事实上，激活 5-HT 受体可能有助于减少与多巴胺刺激相关的运动障碍副作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e49/8378419/522875528625/nihms-1717750-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e49/8378419/ca4ec0a5049f/nihms-1717750-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e49/8378419/8da15508b01b/nihms-1717750-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e49/8378419/522875528625/nihms-1717750-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e49/8378419/ca4ec0a5049f/nihms-1717750-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e49/8378419/8da15508b01b/nihms-1717750-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e49/8378419/522875528625/nihms-1717750-f0003.jpg

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