Exploration of Diazaspiro Cores as Piperazine Bioisosteres in the Development of σ2 Receptor Ligands

Xu, Kuiying; Hsieh, Chia-Ju; Lee, Ji Youn; Riad, Aladdin; Izzo, Nicholas J.; Look, Gary; Catalano, Susan; Mach, Robert H.

doi:10.3390/ijms23158259

Open AccessArticle

Exploration of Diazaspiro Cores as Piperazine Bioisosteres in the Development of σ2 Receptor Ligands

by

Kuiying Xu

¹,

Chia-Ju Hsieh

¹

,

Ji Youn Lee

¹,

Aladdin Riad

¹,

Nicholas J. Izzo

²

,

Gary Look

²,

Susan Catalano

² and

Robert H. Mach

^1,*

¹

Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA

²

Cognition Therapeutics Inc., Pittsburgh, PA 15203, USA

^*

Author to whom correspondence should be addressed.

Int. J. Mol. Sci. 2022, 23(15), 8259; https://doi.org/10.3390/ijms23158259

Submission received: 27 June 2022 / Revised: 19 July 2022 / Accepted: 21 July 2022 / Published: 27 July 2022

(This article belongs to the Special Issue The Intriguing Sigma-1 and Sigma-2 Receptors and Their Potential Therapeutic Roles 2.0)

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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 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.

Keywords: sigma-2 receptors; TMEM97; diazaspiro cores; bioisosteres

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MDPI and ACS Style

Xu, K.; Hsieh, C.-J.; Lee, J.Y.; Riad, A.; Izzo, N.J.; Look, G.; Catalano, S.; Mach, R.H. Exploration of Diazaspiro Cores as Piperazine Bioisosteres in the Development of σ2 Receptor Ligands. Int. J. Mol. Sci. 2022, 23, 8259. https://doi.org/10.3390/ijms23158259

AMA Style

Xu K, Hsieh C-J, Lee JY, Riad A, Izzo NJ, Look G, Catalano S, Mach RH. Exploration of Diazaspiro Cores as Piperazine Bioisosteres in the Development of σ2 Receptor Ligands. International Journal of Molecular Sciences. 2022; 23(15):8259. https://doi.org/10.3390/ijms23158259

Chicago/Turabian Style

Xu, Kuiying, Chia-Ju Hsieh, Ji Youn Lee, Aladdin Riad, Nicholas J. Izzo, Gary Look, Susan Catalano, and Robert H. Mach. 2022. "Exploration of Diazaspiro Cores as Piperazine Bioisosteres in the Development of σ2 Receptor Ligands" International Journal of Molecular Sciences 23, no. 15: 8259. https://doi.org/10.3390/ijms23158259

APA Style

Xu, K., Hsieh, C.-J., Lee, J. Y., Riad, A., Izzo, N. J., Look, G., Catalano, S., & Mach, R. H. (2022). Exploration of Diazaspiro Cores as Piperazine Bioisosteres in the Development of σ2 Receptor Ligands. International Journal of Molecular Sciences, 23(15), 8259. https://doi.org/10.3390/ijms23158259

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Exploration of Diazaspiro Cores as Piperazine Bioisosteres in the Development of σ2 Receptor Ligands

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