The novel, orally active, delta opioid RWJ-394674 is biotransformed to the potent mu opioid RWJ-413216.

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.

Synthesis and evaluation of 4-(N,N-diarylamino)piperidines with high selectivity to the delta-opioid receptor: a combined 3D-QSAR and ligand docking study.

A series of 4-(N,N-diarylamino)piperidines are synthesized and evaluated for high affinity binding and selectivity to the delta-opioid receptor using a combination of 3D-QSAR and molecular docking techniques. Based on experimental ligand binding data to both mu- and delta- opioid receptors, CoMFA fields are generated and applied to identify potential ligand modifications to further optimize lead compounds. Molecular docking experiments to the delta-receptor are also reported that explain the CoMFA trends predicted as well as the differential binding and selectivity displayed by various compounds in the series. An analysis of the binding site model proposed indicates the piperidines take advantage of 3 key sites or binding domains within the delta-receptor. These include an aromatic pocket (approximately 1/3 into the receptor cavity), an aspartic acid residue (which serves as a docking point for the piperidinyl cationic amine) and a hydrophobic pocket at the extracellular boundary of the receptor cavity. Links are established between ligand modification and amino acid composition at these sites in mu and delta, providing new insight to the structural basis to binding and selectivity across the series and for related piperazines (i.e. SNC80 and BW373U86). Results are also presented that indicate delta- and mu-selectivity may be determined at alternate sites, suggesting opioid receptors may display multiple binding domains. The model is further supported by comparisons with opiate binding modes and site directed mutagenesis studies and is finally applied to suggest new strategies in ligand design.

Synthesis and binding affinities of 4-diarylaminotropanes, a new class of delta opioid agonists.

A series of 4-diarylaminotropanes has been prepared. Both endo and exo diastereomeric forms bound to the delta opioid receptor but the endo isomers were more potent and selective versus the mu opioid receptor than the exo isomers. The most potent delta opioid agonist (14) exhibited a delta opioid Ki of 0.2 nM and was 860-fold selective over mu.