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 ( K i  = 2.5–18 nM), and selectivity toward sigma 2 receptor, without cytotoxic effects on SY5Y cells.