将 MLPCN 探针 ML071 持续优化为 hM1 毒蕈碱乙酰胆碱受体的高效激动剂。
Continued optimization of the MLPCN probe ML071 into highly potent agonists of the hM1 muscarinic acetylcholine receptor.
机构信息
Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
出版信息
Bioorg Med Chem Lett. 2012 May 15;22(10):3467-72. doi: 10.1016/j.bmcl.2012.03.088. Epub 2012 Mar 29.
Abstract
This Letter describes the continued optimization of the MLPCN probe molecule ML071. After introducing numerous cyclic constraints and novel substitutions throughout the parent structure, we produced a number of more highly potent agonists of the M(1) mACh receptor. While many novel agonists demonstrated a promising ability to increase soluble APPα release, further characterization indicated they may be functioning as bitopic agonists. These results and the implications of a bitopic mode of action are presented.
摘要
这封信描述了 MLPCN 探针分子 ML071 的持续优化。在对母体结构进行了大量的环状约束和新颖取代后，我们产生了一些更有效的 M1 毒蕈碱受体激动剂。虽然许多新型激动剂显示出有希望增加可溶性 APPα 释放的能力，但进一步的特征表明它们可能作为双位点激动剂发挥作用。这些结果和双位点作用模式的意义将被呈现。
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