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

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

Research output: Contribution to journal › Article › peer-review

2 Scopus citations

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.

Original language	English (US)
Article number	114840
Journal	European Journal of Medicinal Chemistry
Volume	244
DOIs	https://doi.org/10.1016/j.ejmech.2022.114840
State	Published - Dec 15 2022

Keywords

Dopamine 4 receptor
Modulators
SAR
Selectivity
Sigma 1 receptor

ASJC Scopus subject areas

Pharmacology
Drug Discovery
Organic Chemistry

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10.1016/j.ejmech.2022.114840

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

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.",

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T2 - Synthesis, SAR and biological characterization of a piperidine scaffold of σ1 modulators

AU - Tolentino, Kirsten T.

AU - Mashinson, Viktoriya

AU - Sharma, Manish K.

AU - Chhonker, Yashpal S.

AU - Murry, Daryl J.

AU - Hopkins, Corey R.

PY - 2022/12/15

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KW - Dopamine 4 receptor

KW - Modulators

KW - SAR

KW - Selectivity

KW - Sigma 1 receptor

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

Abstract

Keywords

ASJC Scopus subject areas

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