通过比较分子场分析（CoMFA）对3,8-二氮杂双环[4.2.0]辛烷衍生物作为神经元烟碱型乙酰胆碱受体进行3D-QSAR和QSSR研究。
3D-QSAR and QSSR studies of 3,8-diazabicyclo[4.2.0]octane derivatives as neuronal nicotinic acetylcholine receptors by comparative molecular field analysis (CoMFA).
作者信息
Ye Mao, Dawson Marcia I
机构信息
Burnham Institute for Medical Research, La Jolla, CA 92037, USA.
出版信息
Bioorg Med Chem Lett. 2009 Jan 1;19(1):127-31. doi: 10.1016/j.bmcl.2008.11.016. Epub 2008 Nov 9.
High subtype selectivity (alpha4beta2 over alpha2beta3) of neuronal nicotinic acetylcholine receptor (nAChR) agonists is critical for the rational design of less toxic drugs used for the treatment of neurodegenerative and psychiatric diseases. Here, three CoMFA models of pEC(50)(alpha4beta2), pEC(50)(alpha2beta3) and p[EC(50)(alpha4beta2)/EC(50)(alpha2beta3)] (pEC(50)(alpha4beta2)pEC(50)(alpha2beta3)) were developed to study the quantitative structure-activity relationship (QSAR) and quantitative structure-selectivity relationship (QSSR) of the 3,8-diazabicyclo[4.2.0]octane derivatives as nAChRs agonists. The parameters of the three models were 0.584, 0.792, and 0.599 for cross-validated r(2) (r(2)(CV)), 0.924, 0.935 and 0.875 for conventional r(2). Analyses indicated that both the steric and electrostatic factors should be considered in the rational design of more active and selective nAChR agonists.
神经元烟碱型乙酰胆碱受体（nAChR）激动剂的高亚型选择性（α4β2相对于α2β3）对于合理设计用于治疗神经退行性疾病和精神疾病的低毒药物至关重要。在此，开发了pEC(50)(α4β2)、pEC(50)(α2β3)和p[EC(50)(α4β2)/EC(50)(α2β3)]（pEC(50)(α4β2)pEC(50)(α2β3)）的三个比较分子场分析（CoMFA）模型，以研究作为nAChR激动剂的3,8-二氮杂双环[4.2.0]辛烷衍生物的定量构效关系（QSAR）和定量构选关系（QSSR）。三个模型的参数，交叉验证r(2)（r(2)(CV)）分别为0.584、0.792和0.599，传统r(2)分别为0.924、0.935和0.875。分析表明，在合理设计更具活性和选择性的nAChR激动剂时，应同时考虑空间和静电因素。
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