Scuola di Scienze del Farmaco e dei Prodotti della Salute, Università di Camerino, Via S. Agostino 1, 62032 Camerino, Italy.
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, MD 21224, USA.
Eur J Med Chem. 2017 Sep 8;137:327-337. doi: 10.1016/j.ejmech.2017.06.004. Epub 2017 Jun 3.
To obtain novel muscarinic acetylcholine receptor (mAChR) antagonists, the enantiomers of the hybrid compounds 3-5, in which the quinuclidin-3-yloxy fragment of solifenacin and the 6,6-diphenyl-1,4-dioxane-2-yl moiety of 2 linked by an ester or ether spacer were embedded in the same chemical entity, were prepared and evaluated for their affinity at the five mAChR subtypes (M-M). Stereochemistry and the nature of the linker between the quinuclidine moiety and the 1,4-dioxane nucleus play an important role on the affinities of the compounds. The presence of an ether bridge confers higher affinities for all mAChR subtypes to the ligand. Interestingly, the ether enantiomer (R,S)-5 shows the highest affinity at all mAChR subtypes with pK values similar to that of solifenacin at M and higher at the other subtypes. Unlike solifenacin, it shows a preference for M mAChR subtype with respect to the other subtypes. This compound, lacking a permanent positive charge on the nitrogen atom, can be a useful tool for the pharmacological study of mAChRs in the central nervous system.
为了获得新型毒蕈碱乙酰胆碱受体（mAChR）拮抗剂，我们合成了手性化合物 3-5 的对映异构体，其中索利那新的奎宁环-3-氧基片段和 2 的 6,6-二苯基-1,4-二氧六环-2-基部分通过酯或醚间隔基连接在同一化学实体中。对这些化合物在五种 mAChR 亚型（M-M）上的亲和力进行了评价。立体化学和连接奎宁环部分与 1,4-二氧六环核的键的性质对化合物的亲和力起着重要作用。醚桥的存在赋予配体对所有 mAChR 亚型更高的亲和力。有趣的是，醚对映异构体（R,S）-5 在所有 mAChR 亚型上都表现出最高的亲和力，pK 值与索利那新在 M 型上的相似，在其他亚型上更高。与索利那新不同，它对 M mAChR 亚型表现出偏好，而对其他亚型则没有。该化合物氮原子上没有永久正电荷，可作为研究中枢神经系统 mAChRs 的药理学工具。
