Mu-
opioid analgesics are a mainstay in the treatment of acute and
chronic pain of multiple origins, but their side effects, such as
constipation,
respiratory depression, and abuse liability, adversely affect patients. The recent demonstration of the up-regulation and membrane targeting of the
delta-opioid receptor (DOR) following
inflammation and the consequent enhanced
therapeutic effect of delta-
opioid agonists have enlivened the search for delta-
opioid analgesic agents.
JNJ-20788560 [9-(8-azabicyclo-[3.2.1]oct-3-ylidene)-9H-
xanthene-3-
carboxylic acid diethylamide] had an affinity of 2.0 nM for DOR (rat brain cortex binding assay) and a
naltrindole sensitive DOR potency of 5.6 nM (5'-O-(3-[(35)S]thio)
triphosphate assay). The compound had a potency of 7.6 mg/kg p.o. in a rat
zymosan radiant heat test and of 13.5 mg/kg p.o. in a rat Complete
Freund's adjuvant RH test but was virtually inactive in an uninflamed radiant heat test. In limited studies, tolerance was not observed to the antihyperalgesic or antinociceptive effects of the compound. Unlike
ibuprofen,
JNJ-20788560 did not produce gastrointestinal (GI) erosion. Although
morphine reduced GI motility at all doses tested and reached nearly full effect at the highest dose,
JNJ-20788560 did not retard transit at the lowest dose and reached only 11% reduction at the highest dose administered. Unlike
morphine,
JNJ-20788560 did not exhibit
respiratory depression (blood gas analysis), and no withdrawal signs were precipitated by the administration of
opioid (mu or delta) antagonists. Coupled with the previously published lack of
self-administration behavior of the compound by
alfentanil-trained primates, these findings strongly recommend delta-
opioid agonists such as
JNJ-20788560 for the relief of inflammatory
hyperalgesia.