Exploration of Diazaspiro Cores as Piperazine Bioisosteres in the Development of σ2 Receptor Ligands |
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Authors: | Kuiying Xu Chia-Ju Hsieh Ji Youn Lee Aladdin Riad Nicholas J Izzo Gary Look Susan Catalano Robert H Mach |
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Affiliation: | 1.Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; (K.X.); (C.-J.H.); (J.Y.L.); (A.R.);2.Cognition Therapeutics Inc., Pittsburgh, PA 15203, USA; (N.J.I.); (G.L.); (S.C.) |
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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 octahydropyrrolo3,4-b] pyrrole ring system resulted in a loss in affinity for the σ2R. On the other hand, the bridged 2,5-diazabicyclo2.2.1]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. |
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Keywords: | sigma-2 receptors TMEM97 diazaspiro cores bioisosteres |
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