# Drug Repurposing: Conversion of the Peripherally Restricted HIV Protease Inhibitor Amprenavir to Potent, Selective, and CNS-Penetrant Agonists for the Cannabinoid Receptor 2

## TL;DR

This paper describes how a drug originally used for HIV was modified to become a potent and brain-penetrating agonist for a specific cannabinoid receptor.

## Contribution

The study introduces modified amprenavir analogues with high CB2 potency, selectivity, and CNS penetration.

## Key findings

- Modified amprenavir analogues show CB2 potency with EC50s <10 nM.
- Selected compounds demonstrate good half-life and brain exposure in rat studies.
- Molecular docking simulations explain the selectivity of analogues for CB2 over CB1.

## Abstract

Herein, we report the identification of the HIV protease
inhibitor
amprenavir as a selective cannabinoid receptor 2 (CB2)
agonist and describe structure–activity relationship (SAR)
studies toward repurposing this peripherally restricted scaffold for
high CB2 potency and CNS exposure. This exercise yielded
compounds with exceptional CB2 potency (EC50s <10 nM), no appreciable activity at the CB1 receptor,
and high predicted permeability/low P-gp efflux activity. Selected
compounds were profiled in rat i.v. dosing cassettes; several novel
amprenavir analogues displayed good t
1/2 (>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 CB2 and to provide a rationale for the observed selectivity
of this series relative to CB1.