Abstract
Compound (+)-3-((α-R)-α-((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°C using membranes from rat brain or guinea pig cerebellum, the Ki values measured for DPI-3290 at δ-, μ-, and κ-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 δ-, μ-, and κ-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 δ-, μ-, and κ-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 μ-opioid receptors and 6.7 ± 1.6 nM at κ-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.
Footnotes
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DOI: 10.1124/jpet.103.054361.
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ABBREVIATIONS: MVD, mouse vas deferens; DPDPE, [d-Pen2,d-Pen5]-enkephalin; DAMGO, [d-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin; U69593, (5α,7α,8α)-(–)-N-methyl-N-(7-(1-pyrrolidinyl)-1-oxaspiro(4.5) dec-8-yl)burzeneacetamide; nor-BNI, nor-binaltorphimine; CTOP, cyclic [d-Phe-Cys-Tyr-d-Trp-Orn-Thr-Pen-Thr-NH2]; TIPP, (Tyr-Tic-Phe-Phe); %MPE, percent maximal possible effect; GPI, guinea pig ileum; 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.
- Received May 12, 2003.
- Accepted August 21, 2003.
- The American Society for Pharmacology and Experimental Therapeutics
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