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- Title
Exploration of Diazaspiro Cores as Piperazine Bioisosteres in the Development of σ2 Receptor Ligands.
- Authors
Xu, Kuiying; Hsieh, Chia-Ju; Lee, Ji Youn; Riad, Aladdin; Izzo, Nicholas J.; Look, Gary; Catalano, Susan; Mach, Robert H.
- Abstract
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.
- Subjects
PIPERAZINE; BIOISOSTERES; SMALL molecules; COMPUTATIONAL chemistry; RADIOLIGAND assay; HYDROGEN bonding interactions; LIGAND binding (Biochemistry)
- Publication
International Journal of Molecular Sciences, 2022, Vol 23, Issue 15, p8259
- ISSN
1661-6596
- Publication type
Article
- DOI
10.3390/ijms23158259