Biasing μ Opioid Receptors with G Protein Inhibitors to Improve Opioid Analgesics

The development of “safer” opioids is difficult owing to the fact that the undesirable effects of opioid analgesics are all on‐target effects at the μ opioid receptor (MOR). A new exciting approach to avoiding side effects has been development of “biased” MOR agonists that alter receptor conformation to preferentially activate analgesic pathways downstream, and away from pathways that promote undesirable side effects [1]. One such drug, Oliceridine, developed by Trevena pharmaceuticals has shown analgesic efficacy in acute pain with limited side effects in Phase IIb clinical trials. Our laboratory has pioneered an alternate approach to biasing GPCR signalling with small molecules that bind to the Gβγ subunits downstream of receptor activation to selectively modify signals downstream of GPCRs. Two prototype molecules, gallein and M119 potentiate the analgesic potency of morphine, without potentiating side effects typically associated with opioid use including acute tolerance, respiratory depression, constipation, hyperlocomotion, reward preference or physical dependence [2–4]. To identify novel small molecule inhibitors of Gβγ with more drug‐like potential we screened a 140, 000 small molecule library comprised of diversity sets from Maybridge and Chemdiv. 36 compounds passed primary testing, triplicate retesting, dose response analysis, counterscreening for assay interfering compounds and triaging to exclude predicted aggregators, PAINS, toxic or reactive compounds and structures with limited drug‐like potential. The molecules have potencies of 2–100 μM in our primary Alphascreen assay (compared to 4 μM for the control SIGK peptide) and multiple compounds inhibit Gβγ activation of PLCβ in in vitro assays of PLC activity with potency equal to or better than the small molecule gallein. One compound has also shown potentiation of opioid analgesia similar to morphine in mice. The hits possess a variety of novel scaffolds and represent good starting points for further medicinal chemistry optimization and represent possible novel potentiators of opioid analgesia. Support or Funding Information 5 R01GM0817720‐08 This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .