短肽与二苯并二氮杂卓型毒蕈碱型乙酰胆碱受体配体的缀合决定了 MR 选择性。
Conjugation of Short Peptides to Dibenzodiazepinone-Type Muscarinic Acetylcholine Receptor Ligands Determines MR Selectivity.
机构信息
Institute of Pharmacy, Faculty of Chemistry and Pharmacy , University of Regensburg , Universitätsstraße 31 , D-93053 Regensburg , Germany.
Department of Chemistry and Pharmacy, Medicinal Chemistry , Friedrich Alexander University , Nikolaus-Fiebiger-Straße 10 , D-91058 Erlangen , Germany.
出版信息
J Med Chem. 2019 Jun 13;62(11):5358-5369. doi: 10.1021/acs.jmedchem.8b01967. Epub 2019 May 22.
Muscarinic acetylcholine receptors (MRs), comprising five subtypes (MR-MR) in humans, exhibit a high degree of structural similarity. Therefore, subtype-selective MR agonists and antagonists are lacking. We present an approach to highly MR-selective MR antagonists based on the conjugation of di- or tripeptides to MR-preferring dibenzodiazepinone-type MR antagonists. MR selectivity was dependent on the peptide sequence and on the type of linker. The introduction of basic amino acids resulted in improved MR selectivity (e.g., UR-AP148 (48): p K (hMR) of 8.97, ratio of K MR/MR/MR/MR/MR of 49:1:6500:60:400) compared to reported pyridobenzo- and dibenzodiazepinone-type MR ligands. A supposed dualsteric binding mode of the DIBA-peptide conjugates, such as 48, at MRs was supported by molecular dynamics simulations.
毒蕈碱型乙酰胆碱受体（MRs）在人类中由五个亚型（MR-MR）组成，具有高度的结构相似性。因此，缺乏亚型选择性的 MR 激动剂和拮抗剂。我们提出了一种基于二肽或三肽与 MR 偏爱型二苯并二氮杂酮型 MR 拮抗剂缀合的方法，以获得高度选择性的 MR 拮抗剂。MR 选择性取决于肽序列和连接子的类型。引入碱性氨基酸可提高 MR 选择性（例如，UR-AP148（48）：p K （hMR）为 8.97，K MR/MR/MR/MR/MR 的比值为 49:1:6500:60:400），与报道的吡啶并苯并二氮杂酮和二苯并二氮杂酮型 MR 配体相比。分子动力学模拟支持 DIBA-肽缀合物（如 48）在 MR 上的双立体结合模式的假设。
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