Morphing of Ibogaine: A Successful Attempt into the Search for Sigma-2 Receptor Ligands.

Ibogaine, a psychoactive alkaloid, binds strongly to the sigma-2 receptor, which is implicated in neurological disorders such as Alzheimer's disease, schizophrenia, alcohol abuse, and pain. Because ibogaine's serious side effects prevent clinical use, researchers sought ibogaine derivatives with better sigma-2 receptor affinity. They performed a deconstruction of ibogaine's tricyclic moiety and scaffold-hopping of its indole part, using a 3D-QSAR model to predict sigma-2 receptor binding affinities and molecular docking on a homology-modeled sigma-2 receptor to validate top candidates. Pinoline, a carboline derivative, was tested in a radioligand binding assay and showed predicted high micromolar affinity and good selectivity. These results may guide design of simplified ibogaine analogs with improved sigma-2 receptor binding.

Study at a glance

Abstract

Ibogaine is a psychoactive indole alkaloid with high affinity for several targets including the σ₂ receptor. Indeed, extensive data support the involvement of the σ₂ receptor in neurological disorders, including Alzheimer's disease, schizophrenia, alcohol abuse and pain. Due to its serious side effects which prevent ibogaine from potential clinical applications, novel ibogaine derivatives endowed with improved σ₂ receptor affinity may be particularly beneficial. With the purpose to facilitate the investigation of iboga alkaloid derivatives which may serve as templates for the design of selective σ₂ receptor ligands, here we report a deconstruction study on the ibogaine tricyclic moiety and a successive scaffold-hopping of the indole counterpart. A 3D-QSAR model has been applied to predict the σ₂ pKi values of the new compounds, whereas a molecular docking study conducted upon the σ₂ receptor built by homology modeling was used to further validate the best-scored molecules. We eventually evaluated pinoline, a carboline derivative, for σ₂ receptor affinity through radioligand binding assay and the results confirmed the predicted high µM range of affinity and good selectivity. The obtained results could be helpful in the drug design process of new ibogaine simplified analogs with improved σ₂ receptor binding capabilities.