Bonifazi Alessandro, Del Bello Fabio, Mammoli Valerio, Piergentili Alessandro, Petrelli Riccardo, Cimarelli Cristina, Pellei Maura, Schepmann Dirk, Wünsch Bernhard, Barocelli Elisabetta, Bertoni Simona, Flammini Lisa, Amantini Consuelo, Nabissi Massimo, Santoni Giorgio, Vistoli Giulio, Quaglia Wilma
Scuola di Scienze del Farmaco e dei Prodotti della Salute, Università di Camerino , Via S. Agostino 1, 62032 Camerino, Italy.
Institut für Pharmazeutische und Medizinische Chemie, Universität Münster , Corrensstraße 48, 48149 Münster, Germany.
J Med Chem. 2015 Nov 12;58(21):8601-15. doi: 10.1021/acs.jmedchem.5b01214. Epub 2015 Oct 14.
Two series of 1,4-dioxanes (4-11 and 12-19) were rationally designed and prepared to interact either with the phencyclidine (PCP) binding site of the N-methyl-d-aspartate (NMDA) receptor or with σ1 receptors, respectively. The biological profiles of the novel compounds were assessed using radioligand binding assays, and the compounds with the highest affinities were investigated for their functional activity. The results were in line with the available pharmacophore models and highlighted that the 1,4-dioxane scaffold is compatible with potent antagonist activity at NMDA receptor or high affinity for σ1 receptors. The primary amines 6b and 7 bearing a cyclohexyl and a phenyl ring or two phenyl rings in position 6, respectively, were the most potent noncompetitive antagonists at the NMDA receptor with IC50 values similar to those of the dissociative anesthetic (S)-(+)-ketamine. The 5,5-diphenyl substitution associated with a benzylaminomethyl moiety in position 2, as in 18, favored the interaction with σ1 receptors.
合理设计并制备了两个系列的1,4 - 二氧六环（4 - 11和12 - 19），使其分别与N - 甲基 - D - 天冬氨酸（NMDA）受体的苯环利定（PCP）结合位点或σ1受体相互作用。使用放射性配体结合试验评估了新型化合物的生物学特性，并对具有最高亲和力的化合物进行了功能活性研究。结果与现有的药效团模型一致，并突出表明1,4 - 二氧六环支架与NMDA受体处的强效拮抗剂活性或对σ1受体的高亲和力兼容。分别在6位带有环己基和苯环或两个苯环的伯胺6b和7是NMDA受体上最有效的非竞争性拮抗剂，其IC50值与解离麻醉剂（S） - （+） - 氯胺酮相似。如18中所示，与2位的苄基氨基甲基部分相关的5,5 - 二苯基取代有利于与σ1受体的相互作用。
