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

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).

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

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.

6-Sulfonylbenzothiazolones as potential scaffolds for the design of 5-HT6 ligands.

5-HT6 Receptors are relatively recently discovered receptors that interact with cholinergic, glutamatergic, GABAergic and dopaminergic transmission systems. These receptors have been implicated in the CNS system as therapeutic targets in applications such as psychosis, reduction of body weight or Alzheimer's disease. As part of our efforts to develop 5-HT6 antagonists, we explored the benzothiazolone scaffold substituted in position 3 or 6 respectively with ethylamino chains and an aromatic ring connected through a sulfonyl linker. Final compounds were evaluated in radioligand binding assays for their ability to interact with 5-HT6 receptors. Their potential cytotoxic effects were determined on the human neuroblastoma cell line SY5Y. They showed very low cytotoxicity, and one of them has submicromolar affinity for 5-HT6 receptors.