From Haloperidol to new selective sigma receptor ligands

Sigma receptors are now considered a unique class of proteins classified into two subtypes, sigma-1 and sigma-2, with peculiar structure, biological functions, and ligands sensitivity. Sigma-1 receptors have been classified as a protein chaperone at the endoplasmatic reticulum (ER)-mitochondrion interface that regulate Ca2+ signaling and cell survival. Sigma-1 receptors modulate ion channels activity and ER stress, having thus an important role in neurodegenerative disorders. Ligands that specifically target sigma-1 receptors have shown a plethora of pharmacological effects. Specifically, sigma-1 antagonists, in addition to the modulation of opioid antinociception, proved their ability in relieving neuropathic and inflammatory pain and having antiproliferative and antiangiogenic effects, while sigma-1 agonists provided efficacious neuroprotection.1,2 Sigma-2 receptors are overexpressed in a wide variety of cancer tissues and, due to this peculiarity, they have been used for the generation of markers for cancer imaging. Moreover, sigma-2 receptor ligands are known to cause cancer cell death in vitro and in vivo. Recently, sigma-2 receptors have been purified, revealing their identity as the transmembrane protein 97 (TMEM97), an endoplasmic reticulum-resident transmembrane protein that regulates the sterol transporter Niemann-Pick disease protein (NPC1). Thus, sigma receptors represent attractive targets useful for neuropathic pain management and neurodegenerative disorders and as brand new tools for cancer treatment and diagnosis. Haloperidol, a typical neuroleptic agent, shows high affinity for sigma receptors but also a high promiscuous affinity for a panel of targets including the main dopaminergic (D1, D2, D3, D4.2), serotoninergic (5HT1D, 5HT2A) and adrenergic α1 receptors. Considering this, in order to avoid interfering off-target effects, new stereoselective and potent derivatives have been synthesized (Fig.1). For compounds with optimal binding profile, additional pharmacological activities (modulation of opioid analgesia, anticancer and anti-amnesic effects) will be reported.