title: 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.affiliation: Ardent Pharmaceuticals, Inc., 631 United Dr., Suite 200, Durham, NC 27713, USA. pgengo@ardentpharma.com
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Gengo
authors.forename: Hugh O
authors.initials: HO
authors.lastname: Pettit
authors.forename: Scott J
authors.initials: SJ
authors.lastname: O'Neill
authors.forename: Ke
authors.initials: K
authors.lastname: Wei
authors.forename: Robert
authors.initials: R
authors.lastname: McNutt
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Bishop
authors.forename: Kwen-Jen
authors.initials: KJ
authors.lastname: Chang
mesh_terms: D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D001549:Benzamides / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D044482:Benzeneacetamides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D001667:Binding, Competitive / Q000187:drug effects; D001784:Blood Gas Analysis; D001923:Brain Chemistry; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000037:antagonists & inhibitors / Q000494:pharmacology; D020881:Enkephalin, D-Penicillamine (2,5)- / Q000037:antagonists & inhibitors / Q000494:pharmacology; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects; D008297:Male; D009130:Muscle, Smooth / Q000187:drug effects; D009292:Narcotic Antagonists / Q000494:pharmacology; D009294:Narcotics / Q000819:agonists*; D010147:Pain Measurement / Q000187:drug effects; D010879:Piperazines / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D011759:Pyrrolidines / Q000037:antagonists & inhibitors / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D017465:Receptors, Opioid, delta / Q000187:drug effects / Q000378:metabolism; D017473:Receptors, Opioid, kappa / Q000187:drug effects / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000187:drug effects / Q000378:metabolism; D013237:Stereoisomerism; D014649:Vas Deferens / Q000187:drug effects
chemical_list: C480732:3-(alpha-(4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-(3-fluorophenyl)-N-methylbenzamide; D000700:Analgesics; D001549:Benzamides; D044482:Benzeneacetamides; D009292:Narcotic Antagonists; D009294:Narcotics; D010879:Piperazines; D011759:Pyrrolidines; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D020881:Enkephalin, D-Penicillamine (2,5)-; C045444:U 69593