ASP6432, a type 1 lysophosphatidic acid receptor antagonist, reduces urethral function during urine voiding and improves voiding dysfunction

Sakamoto, Kazutoshi; Noguchi, Yukiko; Imazumi, Katsunori; Ueshima, Koji; Ohtake, Akiyoshi; Takeda, Masatoshi; Masuda, Noriyuki

doi:10.1016/j.ejphar.2019.01.014

Cited by 6 publications

(3 citation statements)

References 39 publications

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“…Accordingly, a decrease in urethral tone was demonstrated after injection of the specific ATX inhibitor ONO-8430506 (Saga et al, 2014) or after treatment with the new specific LPA 1 antagonist ASP6462 (Sakamoto et al, 2018), suggesting an endogenous LPA/LPA 1 tone. Interestingly, ASP6462 decreased urethral pressure during urine voiding and improved L-NAME-induced voiding dysfunction, which differs from tamsulosin, underlining important differences between LPA 1 and a1-adrenergic regulations (Sakamoto et al, 2019). Although of significant concern for women, no drug therapy has been approved by health authorities so far, and very few drugs are registered for pure stress incontinence.…”

Section: Discussionmentioning

confidence: 99%

Lysophosphatidic Acid Receptor Agonism: Discovery of Potent Nonlipid Benzofuran Ethanolamine Structures

Guillot

Bail²,

Paul³

et al. 2020

J Pharmacol Exp Ther

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Lysophosphatidic acid (LPA) is the natural ligand for two phylogenetically distinct families of receptors (LPA 1-3, LPA 4-6 ) whose pathways control a variety of physiologic and pathophysiological responses. Identifying the benefit of balanced activation/repression of LPA receptors has always been a challenge because of the high lability of LPA and the limited availability of selective and/or stable agonists. In this study, we document the discovery of small benzofuran ethanolamine derivatives (called CpX and CpY) behaving as LPA 1-3 agonists. Initially found as rabbit urethra contracting agents, their elusive receptors were identified from [ 35 S]GTPgS-binding and b-arrestin2 recruitment investigations and then confirmed by [ 3 H]CpX binding studies (urethra, hLPA 1-2 membranes). Both compounds induced a calcium response in hLPA 1-3 cells within a range of 0.4-1.5-log lower potency as compared with LPA. The contractions of rabbit urethra strips induced by these compounds perfectly matched binding affinities with values reaching the two-digit nanomolar level. The antagonist, KI16425, dose-dependently antagonized CpX-induced contractions in agreement with its affinity profile (LPA 1 $LPA 3 ..LPA 2 ). The most potent agonist, CpY, doubled intraurethral pressure in anesthetized female rats at 3 mg/kg i.v. Alternatively, CpX was shown to inhibit human preadipocyte differentiation, a process totally reversed by KI16425. Together with original molecular docking data, these findings clearly established these molecules as potent agonists of LPA 1-3 and consolidated the pivotal role of LPA 1 in urethra/prostate contraction as well as in fat cell development. The discovery of these unique and less labile LPA 1-3 agonists would offer new avenues to investigate the roles of LPA receptors. SIGNIFICANCE STATEMENTWe report the identification of benzofuran ethanolamine derivatives behaving as potent selective nonlipid LPA 1-3 agonists and shown to alter urethra muscle contraction or preadipocyte differentiation. Unique at this level of potency, selectivity, and especially stability, compared with lysophosphatidic acid, they represent more appropriate tools for investigating the physiological roles of lysophosphatidic acid receptors and starting point for optimization of drug candidates for therapeutic applications.

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Section: Discussionmentioning

confidence: 99%

Lysophosphatidic Acid Receptor Agonism: Discovery of Potent Nonlipid Benzofuran Ethanolamine Structures

Guillot

Bail²,

Paul³

et al. 2020

J Pharmacol Exp Ther

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“…All surgical procedures and measurement of micturition parameters via cystometry were performed based on a previously described method. 19,20 Briefly, a catheter (PE-160; Becton, Dickinson & Co., Franklin Lakes, NJ, USA) for saline infusion into the bladder and collection of residual urine after voiding was inserted into the bladder and connected to a pressure transducer (DX-100; Nihon Kohden, Tokyo, Japan) and infusion pump (TE-331S, STC-528; Terumo Co., Tokyo, Japan) via a three-way tap. Each rat was placed in a Ballman's cage (Natsume Seisakusho Co., Ltd., Tokyo, Japan).…”

Section: Evaluation Of Voiding Function In Rats With Voiding Dysfunct...mentioning

confidence: 99%

“…We hypothesize that a considerable number of patients suffering from lower urinary tract symptoms with various possible pathophysiologies including aging 30 have such a condition but are left underdiagnosed because of a lack of clear urodynamically confirmed DU or BOO. 31 We pharmacologically reproduced this condition by administering a combination of atropine and midodrine at doses lower than those used in previous studies, 19,32,33 and applying the experimental methods we used previously 19,20 (Figure 3). In this model, we used the effects of distigmine at 0.003 mg/kg iv as a benchmark because it significantly enhanced the PNS-induced elevation of IVP (Figure 2C) at the plasma concentration similar to that of the clinically efficacious dose (15 mg/man/d) 34,35 (data not shown).…”

Section: Number Of Stoolsmentioning

confidence: 99%

Muscarinic M₃ positive allosteric modulator ASP8302 enhances bladder contraction and improves voiding dysfunction in rats

Okimoto

Ino

Ishizu

et al. 2022

LUTS

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Objectives Muscarinic M3 (M3) receptors mediate cholinergic smooth muscle contraction of the bladder. Current drugs targeting bladder M3 receptors for micturition disorders have a risk of cholinergic side effects due to excessive receptor activation and insufficient selectivity. We investigated the effect of ASP8302, a novel positive allosteric modulator (PAM) of M3 receptors, on bladder function in rats. Methods Modulation of carbachol‐induced increases in intracellular Ca2+ was assessed in cells expressing rat muscarinic receptors. Potentiation of bladder contractions was evaluated using isolated rat bladder strips and by measuring intravesical pressure in anesthetized rats. Conscious cystometry was performed to investigate the effects on residual urine volume and voiding efficiency in rat voiding dysfunction models induced by the α1‐adrenoceptor agonist midodrine and muscarinic receptor antagonist atropine, and bladder outlet obstruction. To assess potential side effects, the number of stools and tracheal insufflation pressure were measured in conscious and anesthetized rats, respectively. Results ASP8302 demonstrated PAM effects on the rat M3 receptor in cell assays, and augmented cholinergic bladder contractions both in vivo and in vitro. ASP8302 improved voiding efficiency and reduced residual urine volume in two voiding dysfunction models as effectively as distigmine bromide, but unlike distigmine bromide did not affect the number of stools or tracheal insufflation pressure. Conclusions Our results in rats indicate that ASP8302 improves voiding dysfunction by potentiating bladder contraction with fewer effects on cholinergic responses in other organs, and suggest a potential advantage over current cholinomimetic drugs for treating micturition disorders caused by insufficient bladder contraction.

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Treatment of Voiding LUTS

Belal

Birring

Chan

et al. 2019

Lower Urinary Tract Symptoms in Adults

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ASP6432, a type 1 lysophosphatidic acid receptor antagonist, reduces urethral function during urine voiding and improves voiding dysfunction

Cited by 6 publications

References 39 publications

Lysophosphatidic Acid Receptor Agonism: Discovery of Potent Nonlipid Benzofuran Ethanolamine Structures

Lysophosphatidic Acid Receptor Agonism: Discovery of Potent Nonlipid Benzofuran Ethanolamine Structures

Muscarinic M₃ positive allosteric modulator ASP8302 enhances bladder contraction and improves voiding dysfunction in rats

Treatment of Voiding LUTS

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ASP6432, a type 1 lysophosphatidic acid receptor antagonist, reduces urethral function during urine voiding and improves voiding dysfunction

Cited by 6 publications

References 39 publications

Lysophosphatidic Acid Receptor Agonism: Discovery of Potent Nonlipid Benzofuran Ethanolamine Structures

Lysophosphatidic Acid Receptor Agonism: Discovery of Potent Nonlipid Benzofuran Ethanolamine Structures

Muscarinic M3 positive allosteric modulator ASP8302 enhances bladder contraction and improves voiding dysfunction in rats

Treatment of Voiding LUTS

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Product

Resources

About

Muscarinic M₃ positive allosteric modulator ASP8302 enhances bladder contraction and improves voiding dysfunction in rats