Abstract
There is a wealth of information from animal models and clinical opioid-analgesic use that indicates a significant role for opioid receptors in the modulation of bladder activity. The novel benzhydrylpiperazine compound DPI-221 [4-((α-S)-α-((2S,5R)-2,5-dimethyl-4-(3-fluorobenzyl)-1-piperazinyl)benzyl)-N,N-diethylbenzamide] was characterized as having δ receptor selectivity using radioligand binding (Ki = 2.0 ± 0.7 nM, δ receptor; 1800 ± 360 nM, μ receptor; and 2300 ± 680 nM, κ receptor), and agonist activity was demonstrated in the mouse isolated vas deferens where DPI-221 inhibited electrically induced contractions with an IC50 value of 88 ± 7.5 nM. In the guinea pig isolated ileum, DPI-221 had no effect on electrically induced contractions at concentrations as high as 1 μM. Sterile saline was infused (7 ml/h) into the bladder of Sprague-Dawley rats, via a transmural catheter; DPI-221 (1.0 to 20 mg/kg p.o.) significantly increased the interval between micturition events, whereas peak void pressure was not significantly decreased by any dose of DPI-221. The micturition effects of 10 mg/kg p.o. DPI-221 were blocked by naltrindole, indicating a δ receptor mechanism of action. In isolated rat bladder strips, DPI-221 was ineffective at relaxing detrusor muscle precontracted with carbachol. The most crucial safety aspect of δ agonist administration is the incidence of seizure-like convulsions in rodents. DPI-221 produced no convulsions at doses up to 100 mg/kg p.o. in mice, although rapid bolus i.v. injection of 5 mg/kg produced convulsions in 3% of mice tested. These findings indicate a good safety profile for DPI-221 administered orally, with potent efficacy in modifying bladder activity.
Footnotes
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Some of these data were presented at Experimental Biology 2004, Washington, DC, April 17-21, 2004 [Watson MJ, Gengo PJ, Pendergast WJ, Chang JP, Wei V, Sanford IJ, Millard DJ, and Chang K-J (2004) The effects of a novel δ-opioid receptor agonist on micturition in rats. FASEB J18:3191].
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.105.090498.
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ABBREVIATIONS: OAB, overactive bladder; DPDPE, cyclic [d-Pen2,d-Pen5] enkephalin; (±)BW373U86, (±)-4-((α-R*)-α-((2S*,5R*)-4-allyl-2,5-dimethyl-1-piperazinyl-3-hydroxybenzyl)-N,N-diethylbenzamide; DPI-221, 4-((α-S)-α-((2S,5R)-2,5-dimethyl-4-(3-fluorobenzyl)-1-piperazinyl)benzyl)-N,N-diethylbenzamide; DAMGO, [d-Ala,N-Me-Phe,Gly-ol]-enkephalin; U69593, (+)-(5α,7α,8β)-N-methyl-N-(7-(1-pyrrolidinyl)-1 oxaspiro[4,5] dec-8-yl)benzeneacetamide; NTI, naltrindole.
- Received June 17, 2005.
- Accepted July 12, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
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