HOMEPRODUCTSSERVICESCOMPANYCONTACTFAQResearchDictionaryPharmaMobileSign Up FREE or Login

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.

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-((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
Topics
  • 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)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research network!


Choose Username:
Email:
Password:
Verify Password: