Sigma receptors have been widely studied for their functions in many biological systems, particularly in the central nervous system, and are involved in several pathologies in this system such as depression, anxiety, schizophrenia, and neurodegeneration. In addition to CNS pathologies, sigma receptors are highly overexpressed in a number of cancer cell types including breast, ovarian, and lung cancer cell lines. Sigma receptors are non-GPCR chaperone proteins that reside on the ER and aid in proper protein folding. There are two identified sub-types: sigma-1R (σ1R) and sigma-2R (σ2R). The σ1R has been isolated from guinea pig and cloned to determine the receptor as a 223 amino acid protein. This subtype has been the focus of many therapeutic studies for various diseases such as cocaine addiction, depression, pain, Alzheimer’s disease (AD), and cancer. On the other hand, the σ2R has not been as widely studied because it has yet to be cloned; however, the σ2R has been the subject of many cancer studies. The σ2R has been isolated from a PC12 cell line (rat adrenal glands) and recently was putatively identified as the progesterone receptor membrane component-1 (PGRMC1). Ongoing research in our lab has focused on targeting sigma receptors for a therapeutic effect in alcohol addiction, neurodegenerative diseases, and cancer. Synthesis of a privileged scaffold allows us to readily access analogs to gather structure activity relationship (SAR) data to rationally design lead compounds by targeting this therapeutically diverse protein. The library of sigma receptor ligands thus synthesized is commercially screened in receptor binding assays and a <i>C. elegans</i> model of age related, AD patterned neurodegeneration to determine the selectivity, potency, and efficacy of these ligands. SAR evaluation of next-generation analogs are continuously analyzed in order to optimize drug candidates for treating alcohol addiction, neurodegenerative diseases, and various cancers.

Exploiting the Sigma-2 receptor as a therapeutic target for cancer and various CNS diseases

249th National Meeting (2015)

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