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

Recent work suggests that opioids which combine mu agonist and delta antago nist activity may be non-addicting antinociceptive agents. SoRI 9409 (5'-(4 -Chlorophenyl)17-(cyclopropylmethyl)-6,7-didehydro-3,14-dihydroxy-4,5 alpha - epoxypyrido-[2',3':6,7]morphinan) is a naltrexone-derived non-peptide lig and which demonstrates partial mu and kappa agonist activity and antagonist activity at delta receptors. Chronic administration of SoRI 9409 to mice f ailed to produce tolerance to its antinociceptive effect and SoRI 9409 prod uced less withdrawal signs than naloxone in acute and chronic morphine depe ndence models. To further characterize SoRI 9409 we determined its effects in the guanosine 5'-O-(3-[S-35]thio)-triphosphate binding assay. SoRI 9409 demonstrated no agonist activity at cloned mu, delta, or kappa receptors. O ther experiments demonstrated that SoRI 9409 was a potent and selective del ta antagonist (K-i = 0.08 nM) which acted also as an antagonist at mu and k appa receptors. Its profile of activity resembled that of naltrindole (NTI) . Viewed collectively, the in vitro data reported here predict that SoRI 94 09 should be a mu antagonist in vivo, which is not observed. Resolving thes e discrepant findings will require additional research. (C) 2001 Elsevier S cience Inc.