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
| Autor: | Scott J. O'Neill, Peter J. Gengo, Ke Wei, Michael J. Bishop, Robert W. McNutt, Kwen-Jen Chang, Hugh O. Pettit |
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| Rok vydání: | 2003 |
| Předmět: |
Male
Narcotics Pyrrolidines Narcotic Antagonists Analgesic Guinea Pigs Benzeneacetamides Receptors Opioid mu (+)-Naloxone Pharmacology Binding Competitive Piperazines Fentanyl Guinea pig Rats Sprague-Dawley Radioligand Assay Vas Deferens Ileum Receptors Opioid delta medicine Animals Receptor Pain Measurement Brain Chemistry Analgesics business.industry Receptors Opioid kappa Vas deferens Muscle Smooth Stereoisomerism Enkephalin Ala(2)-MePhe(4)-Gly(5) Rats medicine.anatomical_structure Opioid Benzamides Morphine Molecular Medicine Blood Gas Analysis business Enkephalin D-Penicillamine (2 5) medicine.drug |
| Zdroj: | The Journal of pharmacology and experimental therapeutics. 307(3) |
| ISSN: | 0022-3565 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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