Morphing of Ibogaine: A Successful Attempt into the Search for Sigma-2 Receptor Ligands.
International journal of molecular sciences – January 23, 2019
Source: PubMed
Summary
While ibogaine holds promise for neurological conditions like Alzheimer's due to its interaction with the sigma-2 receptor, its severe side effects hinder clinical use. Scientists successfully sought to design safer ibogaine-derived compounds. Employing techniques like molecular docking and scaffold-hopping, they developed novel molecules. A significant achievement was identifying pinoline, a simplified derivative that demonstrated robust and selective binding to the sigma-2 receptor, specifically the tmem97 protein. This breakthrough offers a strong foundation for creating effective new therapies.
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.