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NEUROPHARMACOLOGY

DPI-3290 [(+)-3-((-R)--((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

Ardent Research Laboratories, Ardent Pharmaceuticals, Inc., Durham, North Carolina

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-((-R)--((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 ED₅₀ 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 ED₅₀ value of 0.91 ± 0.22 mg/kg. In comparison, morphine and fentanyl increased antinociception in rats with ED₅₀ values of 2.01 ± 0.0005 and 0.0034 ± 0.00024 mg/kg, respectively, and the ED₅₀ value for morphine-induced changes in pCO₂ was 4.23 ± 0.72 mg/kg, whereas the ED₅₀ 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 µ-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 µg/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 ED₅₀ value for antinociception with the ED₅₀ 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 µ-opioid receptor-mediated hypercapnia.

Address correspondence to: Dr. Peter J. Gengo, Ardent Pharmaceuticals, Inc., 631 United Dr., Suite 200, Durham, NC 27713. E-mail: pgengo{at}ardentpharma.com

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