Recent Advances in the Development of Sigma-1 Receptor Ligands

The existence of two distinct sigma (σ) receptor subtypes was established in the early 1990s. Sigma-1 and sigma-2 receptors (S1Rs and S2Rs, respectively) were shown to possess distinct molecular size, anatomical distribution, and ligand discrimination. S2R is overexpressed in numerous human cancers, and has therapeutic potential for the imaging and treatment of certain tumours. In contrast, S1R is more broadly involved in a wide variety of central nervous system (CNS) diseases including motor disorders, memory deficits, depression, schizophrenia, anxiety, pain, drug addiction, and many more. Since the human S1R was cloned in 1996, numerous high affinity ligands with excellent selectivity for S1R have been developed. This review focuses on recent developments in the generation of structurally diverse S1R-selective ligands and novel therapeutic candidates targeting S1Rs.