BEHAVIORAL-EFFECTS AND RECEPTOR-BINDING AFFINITIES OF FENTANYL DERIVATIVES IN RHESUS-MONKEYS

These studies examined the opioid receptor binding affinities and beha vioral effects of several fentanyl derivatives in rhesus monkeys. OHM3 295, OHM3296, OHM3326 and OHM3463 displayed high affinity for mu (IC50 = 7-66 nM) as compared to kappa (IC50 = 263-3255 nM) or delta (IC50 = 480-4500 nM) receptors as measured by their ability to displace [H-3] (D-Ala(2)-Me-Phe(4), Glyol(5))enkephalin, rolidinyl)1-oxaspiro[4,5]dec -8-yl]benzeneacetamide and [H-3](D-Pen(2)-D-Pen(5))enkephalin, respect ively. All four compounds maintained i.v. self-administration respondi ng at rates above those maintained by saline and below those maintaine d by the mu agonist alfentanil. In drug discrimination studies, OHM346 3, OHM3326 and OHM3296 substituted completely for nalbuphine whereas O HM3295, and a related compound, mirfentanil, substituted partially for nalbuphine. In morphine-treated monkeys, OHM3295 substituted for nalt rexone; in monkeys acutely deprived of morphine, only OHM3463 reversed naltrexone-lever responding. All four compounds had antinociceptive e ffects, although the extent to which these effects were accompanied by respiratory depression or modified by naltrexone, as well as the inte ractions between antinociceptive effects of fentanyl derivatives and a lfentanil, varied markedly among compounds. Thus, OHM3463 shared effec ts with mu agonists (e.g., alfentanil) under all conditions; the other three compounds had opioid agonist effects under only a subset of con ditions. Moreover, one of these compounds (OHM3295) antagonized the di scriminative stimulus and antinociceptive effects of other mu agonists . Collectively, these compounds appear to vary on two dimensions: opio id efficacy and the contribution of nonopioid actions to their antinoc iceptive effects. Together with results obtained with other fentanyl d erivatives (mirfentanil) under similar conditions, results of the curr ent study suggest this chemical class might be especially fertile for the development of novel analgesics that might have reduced toxicity a nd abuse liability as compared to fentanyl and related compounds that are currently used in medicine.