Synthesis and optimization of novel α-phenylglycinamides as selective TRPM8 antagonists

Kobayashi, Jun’ichi; Hirasawa, H.; Ozawa, Tetsuji; Ozawa, Tomonaga; Takeda, Hiroo; Fujimori, Yoshikazu; Nakanishi, Osamu; Kamada, Noboru; Ikeda, Tetsuya

doi:10.1016/j.bmc.2016.11.049

Cited by 14 publications

(19 citation statements)

References 40 publications

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“…Selectivity of KPR for TRPM8 channel is more than 300‐fold against human TRPA1, TRPV1, and TRPV4 channels, and KPR did not show any inhibitory effects for ASIC1a and ASIC3 channels with IC 50 values of more than 10 µM (data not shown).…”

Section: Discussionmentioning

confidence: 95%

“…KPR was synthesized as described previously . N , N ‐dimethyl acetamide (Sigma‐Aldrich, St. Louis, MO) and AA (Wako Pure Chemical Industries, Tokyo, Japan) were used.…”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…We recently developed a TRPM8 antagonist, KPR‐2579 (KPR) . This compound exhibited good efficacy against wet‐dog shakes induced by icilin with a moderate pharmacokinetic profile but without cardiovascular effects and inhibited rhythmic bladder contractions in rats . In the present study, we examined the effects of KPR on body temperature and on bladder hyperactivity, particularly on increased mechanosensitive afferent activity provoked by intravesical acetic acid (AA) instillation in rats.…”

Section: Introductionmentioning

confidence: 99%

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KPR‐2579, a novel TRPM8 antagonist, inhibits acetic acid‐induced bladder afferent hyperactivity in rats

Aizawa

Fujimori

Kobayashi

et al. 2018

Neurourology and Urodynamics

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Section: Discussionmentioning

confidence: 95%

“…KPR was synthesized as described previously . N , N ‐dimethyl acetamide (Sigma‐Aldrich, St. Louis, MO) and AA (Wako Pure Chemical Industries, Tokyo, Japan) were used.…”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

KPR‐2579, a novel TRPM8 antagonist, inhibits acetic acid‐induced bladder afferent hyperactivity in rats

Aizawa

Fujimori

Kobayashi

et al. 2018

Neurourology and Urodynamics

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“…Several new antagonists have been described [124,125], and some of them have been tested in animals for their effects on normal LUT and in models of LUT disorders [80,82,126,127,128,129,130].…”

Section: Trp Channel Agonists and Antagonistsmentioning

confidence: 99%

TRP Channels as Lower Urinary Tract Sensory Targets

Andersson

2019

Medical Sciences

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Several members of the transient receptor potential (TRP) superfamily, including TRPV1, TRPV2, TRPV4, TRM4, TRPM8 and TRPA1, are expressed in the lower urinary tract (LUT), not only in neuronal fibers innervating the bladder and urethra, but also in the urothelial and muscular layers of the bladder and urethral walls. In the LUT, TRP channels are mainly involved in nociception and mechanosensory transduction. Animal studies have suggested the therapeutic potential of several TRP channels for the treatment of both bladder over- and underactivity and bladder pain disorders,; however translation of this finding to clinical application has been slow and the involvement of these channels in normal human bladder function, and in various pathologic states have not been established. The development of selective TRP channel agonists and antagonists is ongoing and the use of such agents can be expected to offer new and important information concerning both normal physiological functions and possible therapeutic applications.

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KPR‐5714, a selective transient receptor potential melastatin 8 antagonist, improves voiding dysfunction in rats with bladder overactivity but does not affect voiding behavior in normal rats

Watanabe

Fujimori

Matsuzawa

et al. 2022

Neurourology and Urodynamics

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Aims: Transient receptor potential melastatin 8 (TRPM8) has a role in the abnormal sensory transduction of the bladder and is involved in the pathophysiology of hyperactivity bladder disorders. The aim of this study is to examine the effects of KPR-5714, a novel and selective TRPM8 antagonist, on voiding dysfunction induced by bladder afferent hyperactivity via mechanosensitive C-fibers in rats. Methods: The effects of intragastric administration of KPR-5714 on bladder overactivity induced by intravesical instillation of 10 mM ATP were investigated using cystometry in conscious female rats. We examined the effects of oral administration of KPR-5714 on voiding behavior using a metabolic cage in normal male rats and rats with an intratesticular injection of 3% acetic acid.Results: In cystometry measurements, the intercontraction interval was decreased by intravesical ATP instillation. KPR-5714 (0.1, 0.3, and 1 mg/kg) dose-dependently prolonged the shortened intercontraction interval provoked by ATP. In voiding behavior measurements, intratesticular injection of acetic acid decreased the mean voided volume and increased voiding frequency. KPR-5714 (0.1 and 0.3 mg/kg) dose-dependently increased the mean voided volume and decreased voiding frequency without affecting the total voided volume in these rats. However, KPR-5714 (1 and 10 mg/kg) did not influence the voiding behavior in normal rats. Conclusion:The present results suggest that KPR-5714 improves voiding dysfunction by inhibiting the enhanced activity of mechanosensitive bladder C-fibers in rats with bladder overactivity and shows no significant change in voiding behavior in normal rats.

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Synthesis and optimization of novel α-phenylglycinamides as selective TRPM8 antagonists

Cited by 14 publications

References 40 publications

KPR‐2579, a novel TRPM8 antagonist, inhibits acetic acid‐induced bladder afferent hyperactivity in rats

KPR‐2579, a novel TRPM8 antagonist, inhibits acetic acid‐induced bladder afferent hyperactivity in rats

TRP Channels as Lower Urinary Tract Sensory Targets

KPR‐5714, a selective transient receptor potential melastatin 8 antagonist, improves voiding dysfunction in rats with bladder overactivity but does not affect voiding behavior in normal rats

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