Morphing of Ibogaine: A Successful Attempt into the Search for Sigma-2 Receptor Ligands.
Int J Mol Sci
; 20(3)2019 Jan 23.
Article
em En
| MEDLINE
| ID: mdl-30678129
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.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Ibogaína
Tipo de estudo:
Prognostic_studies
Idioma:
En
Revista:
Int J Mol Sci
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
Itália