title: JNJ-20788560 [9-(8-azabicyclo[3.2.1]oct-3-ylidene)-9H-xanthene-3-carboxylic acid diethylamide], a selective delta opioid receptor agonist, is a potent and efficacious antihyperalgesic agent that does not produce respiratory depression, pharmacologic tolerance, or physical dependence.
abstract: 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.
authors.affiliation: Research and Early Development, Johnson and Johnson Pharmaceutical Research and Development, Spring House, PA 19477, USA. ecodd@its.jnj.com
authors.forename: Ellen E
authors.initials: EE
authors.lastname: Codd
authors.forename: John R
authors.initials: JR
authors.lastname: Carson
authors.forename: Raymond W
authors.initials: RW
authors.lastname: Colburn
authors.forename: Dennis J
authors.initials: DJ
authors.lastname: Stone
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Van Besien
authors.forename: Sui-Po
authors.initials: SP
authors.lastname: Zhang
authors.forename: Paul R
authors.initials: PR
authors.lastname: Wade
authors.forename: Elizabeth L
authors.initials: EL
authors.lastname: Gallantine
authors.forename: Theo F
authors.initials: TF
authors.lastname: Meert
authors.forename: Lory
authors.initials: L
authors.lastname: Molino
authors.forename: Shirley
authors.initials: S
authors.lastname: Pullan
authors.forename: Christine M
authors.initials: CM
authors.lastname: Razler
authors.forename: Scott L
authors.initials: SL
authors.lastname: Dax
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Flores
mesh_terms: D015760:Alfentanil / Q000494:pharmacology; D000701:Analgesics, Opioid; D000818:Animals; D053961:Azabicyclo Compounds / Q000009:adverse effects / Q000494:pharmacology* / Q000633:toxicity; D006224:Cricetinae; D004361:Drug Tolerance; D005769:Gastrointestinal Motility / Q000187:drug effects; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006358:Hot Temperature; D006930:Hyperalgesia / Q000188:drug therapy*; D007509:Irritants / Q000633:toxicity; D008297:Male; D051379:Mice; D010147:Pain Measurement / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D017465:Receptors, Opioid, delta / Q000819:agonists* / Q000378:metabolism; D012131:Respiratory Insufficiency / Q000139:chemically induced* / Q000503:physiopathology; D012640:Seizures / Q000139:chemically induced; D012646:Self Administration; D013276:Stomach Ulcer / Q000139:chemically induced / Q000473:pathology; D013375:Substance Withdrawal Syndrome / Q000523:psychology; D019966:Substance-Related Disorders / Q000503:physiopathology*; D014966:Xanthenes / Q000009:adverse effects / Q000494:pharmacology* / Q000633:toxicity; D015054:Zymosan
chemical_list: C540165:9-(8-azabicyclo(3.2.1)oct-3-ylidene)-9H-xanthene-3-carboxylic acid diethylamide; D000701:Analgesics, Opioid; D053961:Azabicyclo Compounds; D007509:Irritants; D017465:Receptors, Opioid, delta; D014966:Xanthenes; D015760:Alfentanil; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D015054:Zymosan