RT Journal Article
SR Electronic
T1 The Novel, Orally Active, Delta Opioid RWJ-394674 Is Biotransformed to the Potent Mu Opioid RWJ-413216
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 1273
OP 1279
DO 10.1124/jpet.106.104208
VO 318
IS 3
A1 E. E. Codd
A1 J. R. Carson
A1 R. W. Colburn
A1 S. L. Dax
A1 D. Desai-Krieger
A1 R. P. Martinez
A1 L. A. McKown
A1 L. A. Neilson
A1 P. M. Pitis
A1 P. L. Stahle
A1 D. J. Stone
A1 A. J. Streeter
A1 W. N. Wu
A1 S. P. Zhang
YR 2006
UL http://jpet.aspetjournals.org/content/318/3/1273.abstract
AB 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-[35S]-thio)triphosphate binding assay demonstrated its delta agonist function. Surprisingly given this pharmacologic profile, RWJ-394674 exhibited potent oral antinociception (ED50 = 10.5 μmol/kg or 5 mg/kg) in the mouse hot-plate (48°C) test and produced a moderate Straub tail. Antagonist studies in the more stringent 55°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 β-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. The American Society for Pharmacology and Experimental Therapeutics