MOR(e) partners in crime: a bioassay approach to study µ-opioid receptor dimerization by new synthetic opioids

Since 2009, over 73 new synthetic opioids (NSO) have emerged on the global drug market as reported by the European Monitoring Centre for Drugs and Drug Addiction, rendering this one of the fastest growing groups of New Psychoactive Substances. The very high potency, combined with the high risk of fatal overdoses due to respiratory depression, of NSO poses a serious threat to public health. Since relatively little is known about the pharmacology and toxicology of many newly emerging NSO, further insight into NSO pharmacology will result in improved assessment of harm potential and better understanding of the mechanism of action of opioids in general. This project aims at investigating the hitherto less explored concept of μ-opioid receptor (MOR) di- or multimerization. More specifically, based on the recent findings in the Lab that a class of NSO induces MOR dimerization, this project will study in-depth the molecular mechanism behind this observation. To achieve this, an optimized MOR-MOR interaction assay will be developed, which will be used for structure-activity relationship determination, using a panel of structural analogues of existing NSO. In addition, selected NSO will be pharmacologically evaluated in vivo. The structural basis and mechanism of MOR dimerization will be further elucidated via modelling of MOR and MOR/MOR dimers, combined with the generation of MOR mutants. Additionally, a biosensor capable of assessing wild type MOR-MOR interaction will be developed.