Novel, selective k-opioid receptor agonists determined by virtual screening and their pharmacology

Modulating the GPCR k-opioid receptor is a promising strategy for treating various human diseases, with agonists as potentially safer pain medications than conventional µ-opioid analgesics, as k-opioid receptor activation does not produce respiratory depression or risk of overdose.

applying structure-based virtual screening using 3D pharmacophore models based on the binding mode of the natural k-opioid agonist Salvinorin A, two compounds, SalA-VS-07 and SalA-VS-08 were discovered as novel, nonbasic, potent, and selective k-opioid agonists with a G protein-biased agonist profile. Two 3D pharmacophore-based virtual screening methods were performed in parallel and searched both natural product libraries and synthetic compound libraries. Compounds selected from the virtual screening campaign were experimentally evaluated in vitro for binding at the k-opioid receptor. Radioligand competitive binding and [35S]GTPγS binding assays established SalA-VS-07 and SalA-VS-08 having affinity and potency at the k-opioid receptor in the nanomolar range, with SalA-VS-07 as a partial agonist and SalA-VS-08 as a full agonist at the k-opioid receptor, as well as their selectivity for the k-opioid receptor. In vitro studies on functional properties of Sal-VS-07 and Sal-VS-08 to recruit β-arrestin2 at the k-opioid receptor in the PathHunter β-arrestin2 recruitment assay demonstrated the lack of Sal-VS-07 and Sal-VS-08 to induced β-arrestin2 recruitment after receptor activation, in contrary to the high potency and efficacy of prototypical k-opioid agonists Salvinorin A and U69,593, profiling Sal-VS-07 and Sal-VS-08 as G protein-biased k-opioid agonists. 

The dataset includes experimental in vitro pharmacological data on Sal-VS-07 and Sal-VS-08 as novel, selective k-opioid receptor agonists.