Synthesis and pharmacological evaluation of benzannulated derivatives as potent and selective sigma-1 protein ligands

•A series of sigma-1 ligands was synthesised.•The affinity for sigma-1 and sigma-2 receptors 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.

The σ1 proteins are considered to be a new class of target structures for several central nervous system disorders, including depression, anxiety, psychosis, and Parkinson's and Alzheimer's diseases. Recently, the involvement of these receptors in neuropathic pain and cancer has also been observed. So far, only a few ligands are in clinical trials. In a continuation of our previous studies on the development of σ1 ligands, a new series of benzannulated heterocycles was designed and synthesised. In vitro competition binding assays showed that many of them possessed high σ1 receptor affinity (Ki = 0.6–10.3 nM), and good σ2/σ1 subtype selectivity, without cytotoxic effects on SY5Y cells (human neuroblastoma cell line).

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