OHM3597: A novel fentanyl derivative with morphine‐like behavioral effects in rhesus monkeys

Abstract

AbstractOHM3597, a fentanyl‐like piperidine with a thalidomide‐like moiety, was studied in rhesus monkeys for its behavioral effects and for its effects on lipopolysaccharide (LPS)‐induced production of tumor necrosis factor (TNF)‐α, OHM3597 had morphine‐like discriminative stimulus effects that were antagonized by naltrexone in a manner that was consistent with μ receptor mediation. OHM3597 also had antinociceptive effects, producing a maximal (20 sec) antinociceptive effect in a tail withdrawal procedure with a 50°C stimulus. This effect of OHM3597 also was antagonized by naltrexone in a dose‐related manner. Behavioral effects of this fentanyl derivative had a rapid onset and a relatively short duration of action; discriminative stimulus effects were evident 3 min after subcutaneous (sc) administration of 0.32 mg (0.58 μM)/kg of OHM3597 and the duration of antinociceptive effects produced by 1.0 mg (1.6 μM)/kg (sc) was less than 90 min. OHM3597 also was compared to thalidomide for its effects on LPS‐induced TNF‐α production in peripheral blood mononuclear cells that were obtained from drug‐naive rhesus monkeys. Thalidomide suppressed the production of TNF‐α in a concentration‐dependent manner with concentrations of 10 nM and 1 μM of thalidomide decreasing TNF‐α levels to 81 and 65%, respectively, of control (saline) values. In contrast, up to a concentration of 1 μM, OHM3597 failed to suppress LPS‐induced TNF‐α production. These results demonstrate OHM3597 to be a potent, morphine‐like opioid with a relatively short duration of action. Although OHM3597 did not alter TNF‐α production, a compound with both antinociceptive and immunomodulatory effects might be available within this chemical series and could provide a unique approach to the concurrent treatment of pain and infectious disease. © 1995 Wiley‐Liss, Inc.