Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Cognition Therapeutics Inc., Pittsburgh, PA 15203, USA.
Int J Mol Sci. 2022 Jul 27;23(15):8259. doi: 10.3390/ijms23158259.
A series of σ2R compounds containing benzimidazolone and diazacycloalkane cores was synthesized and evaluated in radioligand binding assays. Replacing the piperazine moiety in a lead compound with diazaspiroalkanes and the fused octahydropyrrolo[3,4-b] pyrrole ring system resulted in a loss in affinity for the σ2R. On the other hand, the bridged 2,5-diazabicyclo[2.2.1]heptane, 1,4-diazepine, and a 3-aminoazetidine analog possessed nanomolar affinities for the σ2R. Computational chemistry studies were also conducted with the recently published crystal structure of the σ2R/TMEM97 and revealed that hydrogen bond interactions with ASP29 and π-stacking interactions with TYR150 were largely responsible for the high binding affinity of small molecules to this protein.
合成了一系列含有苯并咪唑啉酮和二氮杂环烷核心的 σ2R 化合物，并在放射性配体结合测定中进行了评估。用氮杂螺烷和稠合的八氢吡咯并[3,4-b]吡咯环系统替换先导化合物中的哌嗪部分导致对 σ2R 的亲和力丧失。另一方面，桥连的 2,5-二氮杂双环[2.2.1]庚烷、1,4-二氮杂环庚烷和 3-氨基氮杂环丁烷类似物对 σ2R 具有纳摩尔亲和力。还进行了计算化学研究，使用最近发表的 σ2R/TMEM97 晶体结构表明，与 ASP29 的氢键相互作用和与 TYR150 的π-堆积相互作用在很大程度上解释了小分子与该蛋白的高结合亲和力。
