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
Autor: | William Pendergast, Ke Wei, Michael. J. Watson, Jonathon D.S. Holt, Scott J. O'Neill, Peter J. Gengo, Kwen-Jen Chang, Jane P. Chang |
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Rok vydání: | 2005 |
Předmět: |
Agonist
Detrusor muscle Male medicine.medical_specialty Carbachol medicine.drug_class Narcotic Antagonists Guinea Pigs Urinary Bladder Urination Convulsants Pharmacology In Vitro Techniques Muscle Smooth Vascular Piperazines δ-opioid receptor Rats Sprague-Dawley Radioligand Assay Vas Deferens Naltrindole Ileum Internal medicine Receptors Opioid delta medicine Animals Benzhydryl Compounds Receptor Pain Measurement Dose-Response Relationship Drug Chemistry Muscle Smooth Naltrexone Rats Endocrinology medicine.anatomical_structure Molecular Medicine μ-opioid receptor Blood Gas Analysis DPI-221 medicine.drug Muscle Contraction |
Zdroj: | The Journal of pharmacology and experimental therapeutics. 315(2) |
ISSN: | 0022-3565 |
Popis: | 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. |
Databáze: | OpenAIRE |
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