DPI-3290 [(+)-3-((alpha-R)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-(3-fluorophenyl)-N-methylbenzamide]. I. A mixed opioid agonist with potent antinociceptive activity.

Abstract

Compound (+)-3-((alpha-R)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-(3-fluorophenyl)-N-methylbenzamide (DPI-3290), is one of a series of novel centrally acting agents with potent antinociceptive activity that binds specifically and with high affinity to opioid receptors. In saturation equilibrium binding studies performed at 25 degrees C using membranes from rat brain or guinea pig cerebellum, the Ki values measured for DPI-3290 at delta-, mu-, and kappa-opioid receptors were 0.18 +/- 0.02, 0.46 +/- 0.05, and 0.62 +/- 0.09 nM, respectively. In vas deferens isolated from laboratory mice, DPI-3290 decreased electrically induced tension development in a concentration-dependent manner with corresponding IC50 values of 1.0 +/- 0.3, 6.2 +/- 2.0, and 25.0 +/- 3.3 nM at delta-, mu-, and kappa-receptors, respectively. The activity of DPI-3290 in isolated vas deferens tissue was approximately 20,000, 175.8, and 1500 times more efficacious than morphine, and 492, 2.5, and 35 times more efficacious than fentanyl at delta-, mu-, and kappa-receptors, respectively. In ileal strips isolated from guinea pigs, DPI-3290 inhibited tension development with a corresponding IC50 value of 3.4 +/- 1.6 nM at mu-opioid receptors and 6.7 +/- 1.6 nM at kappa-opioid receptors. Intravenous administration of 0.05 +/- 0.007 mg/kg DPI-3290 produced a 50% antinociceptive response in rats. The antinociceptive properties of DPI-3290 were blocked by naloxone (0.5 mg/kg s.c.). Compared with morphine, this study demonstrated that DPI-3290 is more potent and elicited a similar magnitude of antinociceptive activity in the rat, actions mediated by its mixed opioid receptor agonist activity. The marked antinociceptive activity of DPI-3290 will likely provide a means for relieving severe pain in patients that require analgesic treatment.

• Authors: Peter J Gengo, Hugh O Pettit, Scott J O'Neill, Ke Wei, Robert McNutt, Michael J Bishop, Kwen-Jen Chang
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 307 Issue 3 Pg. 1221-6 (Dec 2003) ISSN: 0022-3565 [Print] United States
• PMID: 14534368 (Publication Type: Journal Article)

Chemical References

• 3-(alpha-(4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-(3-fluorophenyl)-N-methylbenzamide
• Analgesics
• Benzamides
• Benzeneacetamides
• Narcotic Antagonists
• Narcotics
• Piperazines
• Pyrrolidines
• Receptors, Opioid, delta
• Receptors, Opioid, kappa
• Receptors, Opioid, mu
• Enkephalin, Ala(2)-MePhe(4)-Gly(5)-
• Enkephalin, D-Penicillamine (2,5)-
• U 69593

Topics

• Analgesics (pharmacology)
• Animals
• Benzamides (antagonists & inhibitors, pharmacology)
• Benzeneacetamides (antagonists & inhibitors, pharmacology)
• Binding, Competitive (drug effects)
• Blood Gas Analysis
• Brain Chemistry
• Enkephalin, Ala(2)-MePhe(4)-Gly(5)- (antagonists & inhibitors, pharmacology)
• Enkephalin, D-Penicillamine (2,5)- (antagonists & inhibitors, pharmacology)
• Guinea Pigs
• Ileum (drug effects)
• Male
• Muscle, Smooth (drug effects)
• Narcotic Antagonists (pharmacology)
• Narcotics (agonists)
• Pain Measurement (drug effects)
• Piperazines (antagonists & inhibitors, pharmacology)
• Pyrrolidines (antagonists & inhibitors, pharmacology)
• Radioligand Assay
• Rats
• Rats, Sprague-Dawley
• Receptors, Opioid, delta (drug effects, metabolism)
• Receptors, Opioid, kappa (drug effects, metabolism)
• Receptors, Opioid, mu (drug effects, metabolism)
• Stereoisomerism
• Vas Deferens (drug effects)