Combined tachykinin receptor antagonist: synthesis and stereochemical structure–activity relationships of novel morpholine analogues

Nishi, Takahide; Ishibashi, Koki; Takemoto, Tsunematsu; Nakajima, Katsuyoshi; Fukazawa, Tetsuya; Iio, Yukiko; Itoh, Kazuhiro; Mukaiyama, Osamu; Yamaguchi, Takeshi

doi:10.1016/s0960-894x(00)00324-3

Cited by 27 publications

(17 citation statements)

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“…, has been confirmed to be an orally active triple neurokinin receptor antagonist [47,48]. Briefly, CS-003 inhibited substance P-induced tracheal vascular permeability, NKA-induced bronchoconstriction and NKB-induced bronchoconstriction in guinea pigs.…”

Section: Animalsmentioning

confidence: 97%

“…All surgeries were conducted under ketamine/ xylazine anesthesia and aseptic conditions. This study was conducted according to the in-house guidelines provided by the Institutional Animal Care and Use Committee of Daiichi Sankyo., has been confirmed to be an orally active triple neurokinin receptor antagonist [47,48]. Briefly, CS-003 inhibited substance P-induced tracheal vascular permeability, NKA-induced bronchoconstriction and NKB-induced bronchoconstriction in guinea pigs.…”

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confidence: 98%

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Involvement of Neurokinin Receptors in the Control of Pulsatile Luteinizing Hormone Secretion in Rats

et al. 2011

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Abstract. It has recently been shown that neurokinin B, a tachykinin, is associated with GnRH pulse generation in sheep and goats. The aim of the present study was to clarify the role of tachykinin receptors in the control of LH secretion in rats. To this end, we evaluated the effect of CS-003, an antagonist for all three neurokinin receptors (NK1, NK2 and NK3 receptors), on pulsatile LH secretion in both sexes of rats with different routes of administration. Both oral and third ventricular administration of CS-003 suppressed LH secretion in both sexes of gonadectomized animals. Furthermore, intact male rats with oral administration of CS-003 showed decreased serum testosterone levels, which might be due to suppressed LH secretion. None of the three subtype-specific neurokinin receptor antagonists showed a significant effect on LH secretion in ovariectomized rats when each antagonist was singly administered. The present results suggest that neurokinins play a role in the control of pulsatile GnRH/LH secretion via multiple neurokinin receptors in both male and female rats. Key words: Luteinizing hormone, Neurokinin, Rat, Receptor (J. Reprod. Dev. 57: [409][410][411][412][413][414][415] 2011) ulsatile gonadotropin-releasing hormone (GnRH)/luteinizing hormone (LH) release is indispensable for regulation of gonadal functions, such as folliculogenesis, spermatogenesis and steroidogenesis, in rodents [1], ruminants [2,3] and primates [4]. The mechanism generating GnRH/LH pulses, called the GnRH pulse generator, has been suggested to be localized in the hypothalamus [5]. Recent studies have revealed that kisspeptin neurons located in the hypothalamus play a central role in regulating GnRH release [6,7]. Kisspeptin neurons have two populations in the hypothalamus [8]: One is located in the hypothalamic arcuate nucleus (ARC), and the other is located in the anteroventral periventricular nucleus (AVPV). Of these two populations, the AVPV kisspeptin neurons have been reported to be involved in the regulation of GnRH/LH surge [9,10]. On the other hand, the role of ARC kisspeptin neurons is still unclear, but several lines of evidence suggest that the population is associated with GnRH pulse generation [11].Recent studies have shown an interesting and essential aspect of the ARC kisspeptin neurons. Most kisspeptin neurons have neurokinin B (NKB) and dynorphin (Dyn) in sheep [12], goats [13] and rodents [14], and thus the neurons have been called KNDy neurons [15]. Colocalization of those three neuropeptides in the ARC neurons might be associated with GnRH pulse generation. It has recently been reported that mutations of genes encoding NKB and its receptor are associated with gonadotropin deficiency in humans [16], and central administration of a selective NKB receptor agonist stimulates LH secretion in sheep [17] and monkeys [18]. These reports indicate the significance of NKB/NK3 signaling in GnRH/gonadotropin release in these animal species. In addition to neurokinin B, nor-BNI, a κ-opioid receptor antagonist (KOR), rev...

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Section: Animalsmentioning

confidence: 97%

mentioning

confidence: 98%

Involvement of Neurokinin Receptors in the Control of Pulsatile Luteinizing Hormone Secretion in Rats

et al. 2011

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“…There was a definite shift to the right in the dose-response curve for NKA. At 1 h post-dose there was a 10-fold difference in the PC 20 values between CS-003 and placebo, at 8 h postdose this difference was 3-fold. In comparison with other clinical trials with tachykinin receptor antagonists, the protective effect of CS-003 against NKA-induced bronchoconstriction was larger.…”

Section: Drug Safetymentioning

confidence: 88%

“…In vitro as well as in vivo antagonistic activity against tachykinin NK 1; NK 2 and NK 3 receptors has been shown. In guinea pigs CS-003 inhibited substance P-induced tracheal vascular hyperpermeability, NKA-induced bronchoconstriction and NKB-induced bronchoconstriction [20].…”

Section: Introductionmentioning

confidence: 92%

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The triple neurokinin-receptor antagonist CS-003 inhibits neurokinin A-induced bronchoconstriction in patients with asthma

Schelfhout

Louis

Lenz

et al. 2006

Pulmonary Pharmacology & Therapeutics

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Abstract:Neurokinin A (NKA) causes bronchoconstriction in asthmatic patients. In vitro both NK 1 and NK 2 receptors can mediate airway contraction. Moreover in guinea pigs, NK 3 receptors facilitate cholinergic neurotransmission. Dual tachykinin NK 1 /NK 2 receptor antagonism results in prevention of NKA-induced bronchoconstriction. We have now examined the effect of a single dose of the triple tachykinin receptor antagonist CS-003 on NKAinduced bronchoconstriction in asthmatics.A double blind, crossover, placebo-controlled trial in 16 mild asthmatics was performed. One single dose of CS-003 (200 mg, solution in distilled water) or matched placebo was given orally on the assessment days. NKAprovocation tests were performed pre-dose and 1,8 and 24 h after dosing.There was a significant shift to the right of the dose-response curve at 1 and 8 h after intake of CS-003. PC 20 was not reached in 12/16 patients at 1 h post-dose and in 5/16 patients at 8h post-dose. This did not occur under placebo treatment.A single dose of 200 mg CS-003 protected significantly against NKA-induced bronchoconstriction at 1 and 8 h post-dose in mild asthmatics.

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Will Modulation of Neuropeptide Receptors Produce the Next Generation of Antipsychotic Drugs? A Focus on the Neurokinin and Neurotensin Systems

Dawson

Smith

Watson

2012

Targets and Emerging Therapies for Schizophrenia

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Combined tachykinin receptor antagonist: synthesis and stereochemical structure–activity relationships of novel morpholine analogues

Cited by 27 publications

References 10 publications

Involvement of Neurokinin Receptors in the Control of Pulsatile Luteinizing Hormone Secretion in Rats

Involvement of Neurokinin Receptors in the Control of Pulsatile Luteinizing Hormone Secretion in Rats

The triple neurokinin-receptor antagonist CS-003 inhibits neurokinin A-induced bronchoconstriction in patients with asthma

Will Modulation of Neuropeptide Receptors Produce the Next Generation of Antipsychotic Drugs? A Focus on the Neurokinin and Neurotensin Systems

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