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-((α-R)-α-((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.
Footnotes
-
DOI: 10.1124/jpet.103.054429.
-
ABBREVIATIONS: DPI-3290, (+)-3-((α-R)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-(3-fluorophenyl)-N-methylbenzamide; BW373U86, (±)-4-((αR*)-α-((2S*,5R*)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide; DPDPE, [d-Pen2,d-Pen5]-enkephalin; MPE, percent maximal possible effect.
- Received May 13, 2003.
- Accepted August 21, 2003.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|