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.
Highlights
First introduced as subtypes of the opioid receptor and as high-affinity phencyclidine binding sites, sigma receptors are recognized as a particular and unique receptor class
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
In the study we report here, we have systematically modified the tricyclic moiety of ibogaine and its indole counterpart using a scaffold-hopping approach, and investigated the ability of the new obtained fragments to bind to the σ2 receptor
Summary
First introduced as subtypes of the opioid receptor and as high-affinity phencyclidine binding sites, sigma receptors are recognized as a particular and unique receptor class. Sigma-1 σ1 receptor is highly expressed in both the central and peripheral nervous system, with involvement in the production of neurotrophic factors and in the protection of the mitochondrial integrity [3,4]. In this view, σ1 receptor agonists represent potential therapeutic agents for the treatment of several neuropsychiatric and neurodegenerative disorders, whereas σ1 receptor antagonists have been reported for their antiproliferative and antiangiogenic effects, in addition to the modulation of pain and drug abuse-related conditions [5,6,7,8,9,10]
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