Dipartimento di Scienze Farmaceutiche Pietro Pratesi, Università degli Studi di Milano, Via Mangiagalli 25, 20133 Milano, Italy.
Eur J Med Chem. 2011 Dec;46(12):5790-9. doi: 10.1016/j.ejmech.2011.09.028. Epub 2011 Sep 24.
A set of structural analogues of spirocyclic quinuclidinyl-Δ(2)-isoxazolines, characterized as potent and selective α7 nicotinic agonists, was prepared and assayed for binding affinity at α7 and α4β2 neuronal nicotinic acetylcholine receptors (nAChRs). The investigated derivatives (3a-3c, 4a-4c, 5a-5c, 6a-6c, and 7a-7c), synthesized via the 1,3-dipolar cycloaddition of nitrile oxides to suitable dipolarophiles, showed an overall reduced affinity at the α7 subtype when compared with their model compounds. Solely Δ(2)-isoxazolines 3a, 3b, and 6c maintained a binding affinity in the nanomolar range at the α7 nAChRs (K(i) = 230, 420 and 700 nM, respectively). The quaternary ammonium salt 6c retained also a noteworthy α7 vs. α4β2 subtype selectivity, whereas 3a and 3b showed a sharp reduction in selectivity compared with 1a and 1b, their quinuclidinyl higher homologues.
一套螺环季铵-Δ(2)-异恶唑啉结构类似物，作为强效和选择性的α7 烟碱型乙酰胆碱受体（nAChRs）激动剂，具有结合亲和力，在α7 和α4β2 神经元烟碱型乙酰胆碱受体进行了检测。通过腈氧化物与合适的偶极子的 1,3-偶极环加成反应合成的研究衍生物（3a-3c、4a-4c、5a-5c、6a-6c 和 7a-7c）与模型化合物相比，在α7 亚型的亲和力总体降低。只有Δ(2)-异恶唑啉 3a、3b 和 6c 在α7 nAChRs 中保持了纳摩尔范围内的结合亲和力（K(i)分别为 230、420 和 700 nM）。季铵盐 6c 还保持了显著的α7 与α4β2 亚型选择性，而 3a 和 3b 与它们的更高同系物 1a 和 1b 相比，选择性明显降低。
