Received for publication March 9, 2006.
Revised June 5, 2006.
Accepted for publication June 5, 2006.

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 bound with high affinity to the delta opioid receptor (0.2 nM), and weaker affinity to the mu opioid receptor (72 nM). GTPS 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 non-selective opioid antagonist naloxone as well as to the delta and mu selective antagonists, naltrindole and -FNA (beta-funaltrexamine), respectively. In vitro studies demonstrated that RWJ-394674 was metabolized by hepatic microsomes to its N-desethyl analog, RWJ-413216, which, in contrast to RWJ-39467, 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 hour. 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.

Key words: analgesia, antinociception, delta opioid, mu opioid, mu/delta interactions, opioid metabolism