From dopamine 4 to sigma 1: Synthesis, SAR and biological characterization of a piperidine scaffold of σ1 modulators

Kirsten T Tolentino; Viktoriya Mashinson; Manish K Sharma; Yashpal S Chhonker; Daryl J Murry; Corey R Hopkins

doi:10.1016/j.ejmech.2022.114840

From dopamine 4 to sigma 1: Synthesis, SAR and biological characterization of a piperidine scaffold of σ1 modulators

Eur J Med Chem. 2022 Dec 15:244:114840. doi: 10.1016/j.ejmech.2022.114840. Epub 2022 Oct 14.

Authors

Kirsten T Tolentino¹, Viktoriya Mashinson¹, Manish K Sharma², Yashpal S Chhonker², Daryl J Murry², Corey R Hopkins³

Affiliations

¹ Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE, 68198-6125, USA.
² Department of Pharmacy Practice and Science, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE, 68198-6125, USA.
³ Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE, 68198-6125, USA; UNMC Center for Drug Discovery, University of Nebraska Medical Center, Omaha, NE, 68198, USA. Electronic address: corey.hopkins@unmc.edu.

PMID: 36283180
DOI: 10.1016/j.ejmech.2022.114840

Abstract

The sigma 1 receptor is a multifunctional receptor with wide distribution in the nervous system and its function has been implicated with a number of neurological disorders including dementia and Alzheimer's disease (AD) and other neurodegenerative disorders. In addition, modulators of σ1 have been advanced into clinical trials for the treatment of pain. Starting from our previously disclosed piperidine scaffold, we have identified a class of potent sigma 1 modulators. This work highlights the key SAR components that lead to the divergence in D₄ and σ1 activity. In addition, we further profile lead compounds in a panel of off-target receptors, in vitro and in vivo pharmacokinetic studies. This has culminated in the discovery of multiple σ1 receptor modulators with properties that will allow for study in animal models.

Keywords: Dopamine 4 receptor; Modulators; SAR; Selectivity; Sigma 1 receptor.

MeSH terms

Alzheimer Disease* / drug therapy
Animals
Dopamine
Ligands
Pain
Piperidines / pharmacology
Piperidines / therapeutic use
Receptors, sigma*

Substances

Dopamine
Receptors, sigma
Piperidines
Ligands