title: 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.
authors.affiliation: Univ Lille Nord de France, F-59000 Lille, France; UDSL, EA 4481, UFR Pharmacie, F-59000 Lille, France. Electronic address: marion.donnier-marechal@univ-lille2.fr.
authors.forename: Marion
authors.initials: M
authors.lastname: Donnier-Maréchal
authors.affiliation: Univ Lille Nord de France, F-59000 Lille, France; UDSL, EA 4481, UFR Pharmacie, F-59000 Lille, France. Electronic address: paul-emmanuel.larchanche@univ-lille2.fr.
authors.forename: Paul-Emmanuel
authors.initials: PE
authors.lastname: Larchanché
authors.affiliation: Univ Lille Nord de France, F-59000 Lille, France; UDSL, EA 4483, UFR Pharmacie, F-59000 Lille, France. Electronic address: delphine.lebroc@univ-lille2.fr.
authors.forename: Delphine
authors.initials: D
authors.lastname: Le Broc
authors.affiliation: Univ Lille Nord de France, F-59000 Lille, France; UDSL, EA 4483, UFR Pharmacie, F-59000 Lille, France. Electronic address: christophe.furman@univ-lille2.fr.
authors.forename: Christophe
authors.initials: C
authors.lastname: Furman
authors.affiliation: Univ Lille Nord de France, F-59000 Lille, France; UDSL, EA 4481, UFR Pharmacie, F-59000 Lille, France. Electronic address: pascal.carato@univ-lille2.fr.
authors.forename: Pascal
authors.initials: P
authors.lastname: Carato
authors.affiliation: Univ Lille Nord de France, F-59000 Lille, France; UDSL, EA 4481, UFR Pharmacie, F-59000 Lille, France. Electronic address: patricia.melnyk@univ-lille2.fr.
authors.forename: Patricia
authors.initials: P
authors.lastname: Melnyk
mesh_terms: D014150:Antipsychotic Agents / Q000009:adverse effects / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002243:Carbolines / Q000009:adverse effects / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D055808:Drug Discovery; D006801:Humans; D019169:Jurkat Cells; D008024:Ligands; D015394:Molecular Structure; D018696:Neuroprotective Agents / Q000009:adverse effects / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010640:Phenothiazines / Q000009:adverse effects / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011869:Radioligand Assay; D017480:Receptors, sigma / Q000378:metabolism*; D000097605:Sigma-1 Receptor
chemical_list: D014150:Antipsychotic Agents; D002243:Carbolines; D008024:Ligands; D018696:Neuroprotective Agents; D010640:Phenothiazines; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor
keywords: Carboline; Phenothiazine; Phenoxazine; Sigma receptors; Tetrahydrobenzofuropyridine