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Carboline- and phenothiazine-derivated heterocycles as potent SIGMA-1 protein ligands.

Abstract：

:Sigma 1 receptors are associated with neurodegenerative and psychiatric disorders. These receptors, via their chaperoning functions that counteract endoplasmic reticulum stress and block neurodegeneration, may serve as a target for a new generation of antidepressants or neuroprotective agents. The involvement of these receptors has also been observed in neuropathic pain and cancer. Only a few ligands, such as Igmesine and Anavex 2-73, have been involved in clinical trials. Thus the development of sigma 1 ligands is of interest to a new generation of drugs. Previous work in our lab underlined the potency of benzannulated bicyclic compounds as interesting ligands. Herein the work was extended to a series of novel tricyclic compounds. Carboline- and phenothiazine-derivated compounds were designed and synthesized. In vitro competition binding assays for sigma 1 and 2 receptors showed that most of them have high affinity for sigma 1 receptor (Ki = 2.5-18 nM), and selectivity toward sigma 2 receptor, without cytotoxic effects on SY5Y cells.

journal_name

Eur J Med Chem

journal_title

European journal of medicinal chemistry

authors

Donnier-Maréchal M,Larchanché PE,Le Broc D,Furman C,Carato P,Melnyk P

doi

10.1016/j.ejmech.2014.10.053

subject

Has Abstract

pub_date

2015-01-07 00:00:00

pages

198-206

eissn

0223-5234

issn

1768-3254

pii

S0223-5234(14)00981-7

journal_volume

89

pub_type

杂志文章

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