An update on the development of drugs for neuropsychiatric disorders: focusing on the sigma(1) receptor ligand

The a, receptor is an intracellular molecule that shares no homology with any mammalian proteins. sigma(1) receptors normally localize at the endoplasmic reticulum and regulate a variety of signal transductions including intracellular Ca2+ dynamics and neurotrophic factor signaling. In the brain, sigma(1) receptors are known to regulate the activity of diverse ion channels via protein-protein interactions. Accumulated evidences strongly indicate that the activation/upregulation of sigma(1) receptors promotes the neuronal differentiation as well as a robust antiapoptotic action. In animals, sigma(1) receptor agonists exhibit an antidepressant-like action. Furthermore, the agonists enhanced neuronal survival eventhough they were administered several hours after a brain ischemia. Thus, primary clinical targets of sigma(1) receptor ligands are proposed to include stroke, neurodegenerative disorders and depression. Ligands for the sigma(1) receptor may constitute a new class of therapeutic drugs targeting an endoplasmic reticular protein.