Novel Sigma-1 receptor antagonists: from opioids to small molecules: what is new?

Sigma-1 (σ₁) receptor has been identified as a chaperone protein that interacts with other proteins, such as N-methyl-D-aspartate (NMDA) and opioid receptors, modulating their activity. σ₁ receptor antagonists have been developed to obtain useful compounds for the treatment of psychoses, pain, drug abuse and cancer. Some interesting compounds such as E-5842 (5) and MS-377 (24), haloperidol and piperazine derivatives, respectively, were endowed with high affinity for σ₁ receptors (K_i σ₁ = 4 and 73 nM; K_i σ₂ = 220 and 6900, respectively). They were developed for the treatment of psychotic disorders and 5 also underwent Phase II clinical trials suggesting interesting potential therapeutic applications. Here, σ₁ receptor antagonists have been grouped based on chemical structure and reviewed according to structure-activity relationship and potential therapeutic role.