DPI-221 [4-((alpha-s)-alpha-((2s,5r)-2,5-dimethyl-4-(3-fluorobenzyl)-1-piperazinyl)benzyl)-N,N-diethylbenzamide]: a novel nonpeptide delta receptor agonist producing increased micturition interval in normal rats.

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-((alpha-S)-alpha-((2S,5R)-2,5-dimethyl-4-(3-fluorobenzyl)-1-piperazinyl)benzyl)-N,N-diethylbenzamide] was characterized as having delta receptor selectivity using radioligand binding (K(i) = 2.0 +/- 0.7 nM, delta receptor; 1800 +/- 360 nM, mu receptor; and 2300 +/- 680 nM, kappa receptor), and agonist activity was demonstrated in the mouse isolated vas deferens where DPI-221 inhibited electrically induced contractions with an IC(50) 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 microM. 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 delta 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 delta 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.
AuthorsJonathon D S Holt, Michael J Watson, Jane P Chang, Scott J O'Neill, Ke Wei, William Pendergast, Peter J Gengo, Kwen-Jen Chang
JournalThe Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 315 Issue 2 Pg. 601-8 (Nov 2005) ISSN: 0022-3565 [Print] United States
PMID16020629 (Publication Type: Journal Article)
Chemical References
  • 4-(alpha-(2,5-dimethyl-4-(3-fluorobenzyl)-1-piperazinyl)benzyl)-N,N-diethylbenzamide
  • Benzhydryl Compounds
  • Convulsants
  • Narcotic Antagonists
  • Piperazines
  • Receptors, Opioid, delta
  • naltrindole
  • Naltrexone
  • Carbachol
  • Animals
  • Benzhydryl Compounds (antagonists & inhibitors, pharmacology)
  • Blood Gas Analysis
  • Carbachol (pharmacology)
  • Convulsants (pharmacology)
  • Dose-Response Relationship, Drug
  • Guinea Pigs
  • Ileum (drug effects)
  • In Vitro Techniques
  • Male
  • Muscle Contraction (drug effects)
  • Muscle, Smooth (drug effects)
  • Muscle, Smooth, Vascular (drug effects)
  • Naltrexone (analogs & derivatives, pharmacology)
  • Narcotic Antagonists (pharmacology)
  • Pain Measurement (drug effects)
  • Piperazines (antagonists & inhibitors, pharmacology)
  • Radioligand Assay
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Opioid, delta (agonists)
  • Urinary Bladder (drug effects)
  • Urination (drug effects)
  • Vas Deferens (drug effects)

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