SoRI 9409, a non-peptide opioid mu receptor agonist/delta receptor antagonist, fails to stimulate [35S]-GTP-gamma-S binding at cloned opioid receptors

Abstract

Recent work suggests that opioids which combine mu agonist and delta antagonist activity may be non-addicting antinociceptive agents. SoRI 9409 (5'-(4-Chlorophenyl)-17-(cyclopropylmethyl)-6,7-didehydro-3,14-dihydroxy-4,5alpha-epoxypyrido-[2',3':6,7]morphinan) is a naltrexone-derived non-peptide ligand which demonstrates partial mu and kappa agonist activity and antagonist activity at delta receptors. Chronic administration of SoRI 9409 to mice failed to produce tolerance to its antinociceptive effect and SoRI 9409 produced less withdrawal signs than naloxone in acute and chronic morphine dependence models. To further characterize SoRI 9409 we determined its effects in the guanosine 5'-O-(3-[35S]thio)-triphosphate binding assay. SoRI 9409 demonstrated no agonist activity at cloned mu delta, or kappa receptors. Other experiments demonstrated that SoRI 9409 was a potent and selective delta antagonist (K(i) = 0.08 nM) which acted also as an antagonist at mu and kappa receptors. Its profile of activity resembled that of naltrindole (NTI). Viewed collectively, the in vitro data reported here predict that SoRI 9409 should be a mu antagonist in vivo, which is not observed. Resolving these discrepant findings will require additional research.