OHM3597 - A NOVEL FENTANYL DERIVATIVE WITH MORPHINE-LIKE BEHAVIORAL-EFFECTS IN RHESUS-MONKEYS

OHM3597, a fentanyl-like piperidine with a thalidomide-like moiety, wa s studied in rhesus monkeys for its behavioral effects and for its eff ects on lipopolysaccharide (LPS)-induced production of tumor necrosis factor (TNF)-alpha. OHM3597 had morphine-like discriminative stimulus effects that were antagonized by naltrexone in a manner that was consi stent with mu receptor mediation. OHM3597 also had antinociceptive eff ects, producing a maximal (20 sec) antinociceptive effect in a tail wi thdrawal procedure with a 50 degrees C stimulus. This effect of OHM359 7 also was antagonized by naltrexone in a dose-related manner. Behavio ral effects of this fentanyl derivative had a rapid onset and a relati vely short duration of action; discriminative stimulus effects were ev ident 3 min after subcutaneous (sc) administration of 0.32 mg (0.58 mu M)/kg of OHM3597 and the duration of antinociceptive effects produced by 1.0 mg (1.6 mu M)/kg (sc) was less than 90 min. OHM3597 also was c ompared to thalidomide for its effects on LPS-induced TNF-or productio n in peripheral blood mononuclear cells that were obtained from drug-n aive rhesus monkeys. Thalidomide suppressed the production of TNF-alph a in a concentration-dependent manner with concentrations of 10 nM and 1 mu M of thalidomide decreasing TNF-alpha levels to 81 and 65%, resp ectively, of control (saline) values. In contrast, up to a concentrati on of 1 mu M, OHM3597 failed to suppress LPS-induced TNF-alpha product ion. These results demonstrate OHM3597 to be a potent, morphine-like o pioid with a relatively short duration of action. Although OHM3597 did not alter TNF-alpha production, a compound with both antinociceptive and immunomodulatory effects might be available within this chemical s eries and could provide a unique approach to the concurrent treatment of pain and infectious disease. (C) 1995 Wiley-Liss, Inc.