Drug Repurposing: Conversion of the Peripherally Restricted HIV Protease Inhibitor Amprenavir to Potent, Selective, and CNS-Penetrant Agonists for the Cannabinoid Receptor 2
Abstract
High Resolution Image Download MS PowerPoint Slide Herein, we report the identification of the HIV protease inhibitor amprenavir as a selective cannabinoid receptor 2 (CB 2 ) agonist and describe structure–activity relationship (SAR) studies toward repurposing this peripherally restricted scaffold for high CB 2 potency and CNS exposure. This exercise yielded compounds with exceptional CB 2 potency (EC 50 s 2 h), moderate plasma clearance, and appreciable brain exposure. Additionally, fully flexible protein–ligand docking studies with molecular dynamics (MD) simulations were used to predict the most likely mode of interaction of highly potent analogue VU6077967 with CB 2 and to provide a rationale for the observed selectivity of this series relative to CB 1 .
Fields of Study & Subjects
Cannabis and Cannabinoid Research
Forensic Toxicology and Drug Analysis
Psychedelics and Drug Studies
Publication details
- Journal / source
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Volume
- 69
- Issue
- 4
- Pages
- 4187–4207
- Publication date
- 5 February 2026
- Language
- EN