title: The novel, orally active, delta opioid RWJ-394674 is biotransformed to the potent mu opioid RWJ-413216.
abstract: Although the mu opioid receptor is the primary target of marketed opioid analgesics, several studies suggest the advantageous effect of combinations of mu and delta opioids. The novel compound RWJ-394674 [N,N-diethyl-4-[(8-phenethyl-8-azabicyclo]3.2.1]oct-3-ylidene)-phenylmethyl]-benzamide]; bound with high affinity to the delta opioid receptor (0.2 nM) and with weaker affinity to the mu opioid receptor (72 nM). 5'-O-(3-[(35)S]-thio)triphosphate binding assay demonstrated its delta agonist function. Surprisingly given this pharmacologic profile, RWJ-394674 exhibited potent oral antinociception (ED(50) = 10.5 micromol/kg or 5 mg/kg) in the mouse hot-plate (48 degrees C) test and produced a moderate Straub tail. Antagonist studies in the more stringent 55 degrees C hot-plate test demonstrated the antinociception produced by RWJ-394674 to be sensitive to the nonselective opioid antagonist naloxone as well as to the delta- and mu-selective antagonists, naltrindole and beta-funaltrexamine, respectively. In vitro studies demonstrated that RWJ-394674 was metabolized by hepatic microsomes to its N-desethyl analog, RWJ-413216 [N-ethyl-4-[(8-phenethyl-8-azabicyclo[3.2.1]oct-3-ylidene)-phenylmethyl]-benzamide], which, in contrast to RWJ-394674, had a high affinity for the mu rather than the delta opioid receptor and was an agonist at both. Pharmacokinetic studies in the rat revealed that oral administration of RWJ-394674 rapidly gave rise to detectable plasma levels of RWJ-413216, which reached levels equivalent to those of RWJ-394674 by 1 h. RWJ-413216 itself demonstrated a potent oral antinociceptive effect. Thus, RWJ-394674 is a delta opioid receptor agonist that appears to augment its antinociceptive effect through biotransformation to a novel mu opioid receptor-selective agonist.
authors.affiliation: Johnson & Johnson Pharmaceutical Research and Development, Spring House, PA 19477, USA. ecodd@prdus.jnj.com
authors.forename: E E
authors.initials: EE
authors.lastname: Codd
authors.forename: J R
authors.initials: JR
authors.lastname: Carson
authors.forename: R W
authors.initials: RW
authors.lastname: Colburn
authors.forename: S L
authors.initials: SL
authors.lastname: Dax
authors.forename: D
authors.initials: D
authors.lastname: Desai-Krieger
authors.forename: R P
authors.initials: RP
authors.lastname: Martinez
authors.forename: L A
authors.initials: LA
authors.lastname: McKown
authors.forename: L A
authors.initials: LA
authors.lastname: Neilson
authors.forename: P M
authors.initials: PM
authors.lastname: Pitis
authors.forename: P L
authors.initials: PL
authors.lastname: Stahle
authors.forename: D J
authors.initials: DJ
authors.lastname: Stone
authors.forename: A J
authors.initials: AJ
authors.lastname: Streeter
authors.forename: W N
authors.initials: WN
authors.lastname: Wu
authors.forename: S P
authors.initials: SP
authors.lastname: Zhang
mesh_terms: D000284:Administration, Oral; D000701:Analgesics, Opioid / Q000378:metabolism* / Q000494:pharmacology*; D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000378:metabolism / Q000494:pharmacology*; D005260:Female; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D017465:Receptors, Opioid, delta / Q000819:agonists*; D017450:Receptors, Opioid, mu / Q000819:agonists*
chemical_list: D000701:Analgesics, Opioid; D019086:Bridged Bicyclo Compounds, Heterocyclic; C514018:N,N-diethyl-4-((8-phenethyl-8-azabicyclo(3.2.1)oct-3-ylidene)phenylmethyl)benzamide; C514019:N-ethyl-4-((8-phenethyl-8-azabicyclo(3.2.1)oct-3-ylidene)phenylmethyl)benzamide; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu