Discovery of Iboga-Derived Ligands for the Sigma‑2 Receptor

Substance use disorder (SUD) is a mental condition that affects a person’s brain and behavior, leading to a lack of control with alcohol, drug, and medication use. The lack of efficacious and novel treatments for SUD is a growing concern. As such, we have synthesized a series of iboga alkaloid derivatives and evaluated their receptor binding profiles against a panel of CNS-based proteins, which were performed at the National Institute of Mental Health Psychoactive Drug Screening Program. These studies revealed two compounds that exhibit high affinity for the sigma-2 receptor and introduce the iboga alkaloid framework as a new scaffold for the development of sigma-2 ligands.