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

•A series of 22 tricyclic sigma-1 ligands was synthesized.•The affinity for sigma-1 and sigma-2 receptor was determined.•Most ligands showed nanomolar affinity for sigma-1 receptor.•A good selectivity towards sigma-2 was obtained.•A very low cytotoxicity was measured on SY5Y cells.

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.

Graphical abstractA series of tricyclic derivatives were synthesised as sigma 1 ligands. Some of them showed excellent affinity for sigma 1 receptor and selectivity for sigma 2 receptor. The cytotoxic effects were also evaluated.Figure optionsDownload full-size imageDownload as PowerPoint slide