Effect of ASP2205 fumarate, a novel 5-HT 2C receptor agonist, on urethral closure function in rats

The pharmacological profile of ASP2205 fumarate (ASP2205), a novel 5-HT receptor agonist, was evaluated in vitro and in vivo. ASP2205 showed potent and selective agonistic activity for the human 5-HT receptor, with an EC of 0.85 nM in the intracellular Ca mobilization assay. Rat 5-HT receptor was al...

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Published inJournal of pharmacological sciences Vol. 139; no. 4; p. 333
Main Authors Ishigami, Takao, Ueshima, Koji, Ukai, Masashi, Asai, Norio, Takamatsu, Hajime, Yokono, Masanori, Takeda, Masahiro, Masuda, Noriyuki
Format Journal Article
LanguageEnglish
Published Japan 01.04.2019
Subjects
Animals
Azepines
Dose-Response Relationship, Drug
Female
Fumarates - pharmacology
Fumarates - therapeutic use
Pressure
Quinolines
Rats, Sprague-Dawley
Reflex - drug effects
Serotonin 5-HT2 Receptor Agonists - pharmacology
Serotonin 5-HT2 Receptor Agonists - therapeutic use
Urethra - innervation
Urethra - physiology
Urethra - physiopathology
Urinary Incontinence, Stress - prevention & control
Leak point pressure
Urethral closure response
ASP2205
Urethral pressure
5-HT(2C) receptor
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Summary:The pharmacological profile of ASP2205 fumarate (ASP2205), a novel 5-HT receptor agonist, was evaluated in vitro and in vivo. ASP2205 showed potent and selective agonistic activity for the human 5-HT receptor, with an EC of 0.85 nM in the intracellular Ca mobilization assay. Rat 5-HT receptor was also activated by ASP2205 with an EC of 2.5 nM. Intraduodenal administration (i.d.) of ASP2205 (0.1-1 mg/kg) significantly elevated the leak point pressure (LPP) in anesthetized rats in a dose-dependent manner. This ASP2205 (0.3 mg/kg i.d.)-induced LPP elevation was inhibited by SB242084 (0.3 mg/kg i.v.), a selective 5-HT receptor antagonist. Urethral closure responses induced by intravesical pressure loading in rats were enhanced by ASP2205 (0.3 mg/kg i.v.), which was abolished by pretreatment with SB242084 (0.3 mg/kg i.v.) and bilateral transection of the pudendal nerve. In contrast, ASP2205 (0.3 mg/kg i.v.) did not change the resting urethral pressure in rats. These results indicate that ASP2205 can enhance the pudendal nerve-mediated urethral closure reflex via the 5-HT receptor, resulting in the prevention of involuntary urine loss.
ISSN:1347-8648