Evaluation of Sigma Receptor Drugs

Abstract

Sigma receptors (σ-R) are unique mammalian proteins with two well-characterized subtypes (σ1 and σ2). They are widely distributed in the central nervous system (CNS) and periphery, and have been increasingly implicated in the pathophysiology of virtually all major CNS disorders such as stroke, Alzheimer’ disease and Parkinson’s disease. In addition, both subtypes are over expressed in various tumour cells including breast cancer, prostate cancer and pancreatic cancer. Hence σ-R ligands are an attractive target for the development of drugs for treatment of cancer and neurodegenerative diseases. However, since the discovery of the σ-R in 1976, no selective σ-R ligand has undergone successful clinical development that has progressed through to market approval, despite their promising success in in vitro and in vivo studies. Exploring the pharmacological profile of 39 new σ-R ligands developed in our group, we propose a new translationally relevant methodology to screen σ-R ligands by examining the potency of these compound using “horizontal screening”, where compounds are tested in a variety of assays, probing functional outcomes that are not necessarily related. We have selected assays that are believed to differentiate the activity between compounds that act as either agonist or antagonist at σ-R to assess the possibility of using such assays as a tool to better categorize newly developed σ-R compounds. We hypothesized that this in vitro horizontal methodology might help to make more successful decisions to target compounds with a more complex biological profile towards further investigation for the disease that the compound is most effective against, enabling potentially a more successful outcome in in vivo testing as well as in clinical trials.