Ghandi Mehdi, Sherafat Fatemeh, Sadeghzadeh Masoud, Alirezapour Behrouz
School of Chemistry, College of Science, University of Tehran, PO Box 14155 6455, Tehran, Iran.
School of Chemistry, College of Science, University of Tehran, PO Box 14155 6455, Tehran, Iran.
Bioorg Med Chem Lett. 2016 Jun 1;26(11):2676-9. doi: 10.1016/j.bmcl.2016.04.010. Epub 2016 Apr 6.
New spirocyclic-2,6-diketopiperazine derivatives containing benzylpiperidine and cycloalkane moieties were synthesized by a one-pot two-step sequential Ugi/intramolecular N-amidation process in moderate to good yields. The in vitro ligand-binding profile studies performed on the sigma-1 and sigma-2 receptors revealed that the σ1 affinities and subtype selectivities of three spirocyclic piperidine derivatives are generally comparable to those of spirocycloalkane analogues. Compared to the low σ1 affinities obtained for cycloalkyl-substituted spirocyclic-2,6-diketopiperazines with n=2, those with n=1 proved to have optimal fitting with σ2 subtype by exhibiting higher affinities. Moreover, the best binding affinity and subtype selectivity was identified for compound 3c with Kiσ1=5.9±0.5nM and Kiσ2=563±21nM as well as 95-fold σ1/σ2 selectivity ratio, respectively.
通过一锅两步连续的乌吉/分子内N-酰胺化过程，以中等至良好的产率合成了含有苄基哌啶和环烷烃部分的新型螺环-2,6-二酮哌嗪衍生物。对σ1和σ2受体进行的体外配体结合谱研究表明，三种螺环哌啶衍生物的σ1亲和力和亚型选择性通常与螺环烷类似物相当。与n = 2的环烷基取代的螺环-2,6-二酮哌嗪获得的低σ1亲和力相比，n = 1的那些被证明通过表现出更高的亲和力而与σ2亚型具有最佳匹配。此外，化合物3c的最佳结合亲和力和亚型选择性分别为Kiσ1 = 5.9±0.5nM和Kiσ2 = 563±21nM以及95倍的σ1/σ2选择性比。
