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

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...

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Bibliographic Details
Published in:European journal of medicinal chemistry 2022-12, Vol.244, p.114840-114840, Article 114840
Main Authors: Tolentino, Kirsten T., Mashinson, Viktoriya, Sharma, Manish K., Chhonker, Yashpal S., Murry, Daryl J., Hopkins, Corey R.
Format: Article
Language:English
Subjects:
Dopamine 4 receptor
Modulators
SAR
Selectivity
Sigma 1 receptor
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Summary: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. [Display omitted] •An SAR campaign from D4 antagonists to sigma 1 modulators is presented.•Key SAR points are highlighted in the manuscript which identify key areas where the D4 and σ1 binding diverge.•In vitro and in vivo PK is also presented showing these compounds to be highly brain penetrant.•Selectivity data is presented showing these compounds are highly selective for the σ1 receptor.
ISSN:0223-5234
1768-3254
DOI:10.1016/j.ejmech.2022.114840