Selective Sigma-1 (sig1) Receptor Antagonists: Emerging Target for the Treatment of Neuropathic Pain

A large number of therapeutic roles have been proposed for sig1 receptors but the involvement of sig1 receptor in non-acute pain had not been well explored up to now. sig1 receptor knock-out mice became available offering us the possibility to study the role of sig1 receptor in nociception, particularly in models where central sensitization processes play a significant role. Given the attractive therapeutic potential, we have developed a chemical program aimed at the discovery of novel and selective sig1 ligands. Herein we discuss the rational basis of this approach and report preliminary pharmacological results of several chemical series and aspects of their structure-activity relationship on sig1 receptor. Functional data in pain models are presented mainly on one series that provide evidence to consider selective sig1 receptor antagonists an innovative and alternative approach for treating neuropathic pain.