GTP release-selective agonists prolong opioid analgesic efficacy

GTP release-selective agonists can prolong opioid analgesia by biasing mu opioid receptor signaling toward GTP release rather than GTP binding. The study shows that agonists can have state-selective affinities that promote GTP release versus GTP binding, and that this dissociation can be measured experimentally using nucleotide binding and release assays. The researchers identify two release-preferring compounds (muzepan1 and muzepan2). In mice, marginally efficacious doses of the release-preferring agonist enhance and prolong the antinociceptive effects of morphine and fentanyl, without increasing key adverse effects of fentanyl on respiratory and cardiac measures in their tested readouts. The work proposes that active-state selectivity could help “bifurcate” therapeutic versus harmful physiological responses by altering downstream engagement kinetics and selectivity.