title: DPI-3290 [(+)-3-((alpha-R)-alpha-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-(3-fluorophenyl)-N-methylbenzamide]. II. A mixed opioid agonist with potent antinociceptive activity and limited effects on respiratory function.
abstract: Allyl-2,5-dimethyl-1-piperazines have been of interest as analgesic agents for the management of moderate-to-severe pain. In this study, we compared the antinociceptive properties and respiratory depressant activity of one such agent, (+)-3-((alpha-R)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-(3-fluorophenyl)-N-methylbenzamide (DPI-3290), with those of established narcotic analgesics, morphine and fentanyl. Intravenous administration of DPI-3290 in conscious laboratory rats increased antinociception in a dose-dependent manner with a corresponding ED(50) value of 0.05 +/- 0.0072 mg/kg. Simultaneous measurement of arterial blood gas in animals treated with DPI-3290 demonstrated dose-dependent increases in pCO2 with an ED(50) value of 0.91 +/- 0.22 mg/kg. In comparison, morphine and fentanyl increased antinociception in rats with ED(50) values of 2.01 +/- 0.0005 and 0.0034 +/- 0.00024 mg/kg, respectively, and the ED(50) value for morphine-induced changes in pCO2 was 4.23 +/- 0.72 mg/kg, whereas the ED(50) value for fentanyl-induced changes in pCO2 was 0.0127 +/- 0.0035 mg/kg. A separate series of experiments were designed to examine the effects of DPI-3290 on mu-opioid receptor induced antinociception and hypercapnia. Intravenous bolus doses of DPI-3290 that ranged from 0.2 to 1.0 mg/kg had no effect on antinociception mediated by alfentanil (2 microg/kg/min i.v.) but reduced hypercapnia by approximately 50%. Results from these studies demonstrate the equivalent antinociceptive efficacy of DPI-3290, morphine, and fentanyl but dramatic differences in the hypercapnia that antinociceptive doses of these drugs produce. When measured simultaneously, DPI-3290 had an 18.2-fold difference in the ratio comparing the ED(50) value for antinociception with the ED(50) value for changes in pCO2; this ratio was 2.1 for morphine and 3.7 for fentanyl. Furthermore, DPI-3290 reduced the alfentanil-mediated hypercapnia without any effect on antinociception. Together, the balanced opioid agonist activity of DPI-3290 may provide a means of powerful analgesia while mitigating the mu-opioid receptor-mediated hypercapnia.
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: Ying Fu
authors.initials: YF
authors.lastname: Su
authors.forename: Robert
authors.initials: R
authors.lastname: McNutt
authors.forename: Kwen-Jen
authors.initials: KJ
authors.lastname: Chang
mesh_terms: D015760:Alfentanil / Q000494:pharmacology; D000700:Analgesics / Q000494:pharmacology*; D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D002245:Carbon Dioxide / Q000097:blood; D004305:Dose-Response Relationship, Drug; D006863:Hydrogen-Ion Concentration; D007262:Infusions, Intravenous; D008297:Male; D009294:Narcotics / Q000819:agonists*; D010100:Oxygen / Q000097:blood; D010101:Oxygen Consumption / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D017465:Receptors, Opioid, delta / Q000819:agonists; D017450:Receptors, Opioid, mu / Q000819:agonists; D012129:Respiratory Function Tests; D012137:Respiratory System / Q000187:drug effects*
chemical_list: C480732:3-(alpha-(4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-(3-fluorophenyl)-N-methylbenzamide; D000700:Analgesics; D000701:Analgesics, Opioid; D001549:Benzamides; D009294:Narcotics; D010879:Piperazines; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; D002245:Carbon Dioxide; D015760:Alfentanil; D010100:Oxygen