The novel NK1 receptor antagonist MK–0869 (L–754,030) and its water soluble phosphoryl prodrug, L–758,298, inhibit acute and delayed cisplatin-induced emesis in ferrets

Tattersall, F.D.; Rycroft, W.; Cumberbatch, M.; Mason, G.S.; Tye, Spencer J.; Williamson, David J.; HALE, J; Mills, Sander G.; Finke, Paul E.; MacCoss, Malcolm; Sadowski, S.; Ber, Elżbieta; Cascieri, Margaret A.; Hill, R.G.; MacIntyre, D. Euan; Hargreaves, Richard

doi:10.1016/s0028-3908(99)00172-0

Cited by 128 publications

(88 citation statements)

References 35 publications

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“…A breakthrough in the development of NK1R antagonists, achieved by random screening of chemical libraries, was the discovery of non-peptide compounds, such as L-733.138, L-733.060 and L-703.606, which showed a great affinity for the NK1R. By improving the pharmacokinetic properties of L-733.060, Merck Frosst developed the molecule MK860 or aprepitant (96). Aprepitant, or its commercial name Emend ® , is the first NK1R antagonist approved by the Food and Drug Administration (FDA) and Health Canada in 2009 for its antiemetic properties.…”

Section: The Substance P/neurokinin-1 Receptormentioning

confidence: 99%

Therapeutic Innovations for Targeting Hepatoblastoma

Garnier

Ilmer

Kappler

et al. 2016

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Section: The Substance P/neurokinin-1 Receptormentioning

confidence: 99%

Therapeutic Innovations for Targeting Hepatoblastoma

Garnier

Ilmer

Kappler

et al. 2016

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“…Thus, the IC 50 for HEK 293 fibroblast cells was approximately three times higher than the IC 50 for tumor cells, 30 as occurring in the melanoma cell lines studied here. Indeed, in the host, aprepitant exerts beneficial effects in a dose-dependent manner, such as antiemetic, 29 antidepressant, 27 anxiolytic, 28 anti-inflammatory, 42 analgesic, 43 hepatoprotector 42 and neuroprotector. 44 In summary, we describe for the first time the presence of several isoforms of the NK-1 receptor in MEL HO, COLO 858 and COLO 679 human malignant melanoma cell lines.…”

Section: Nk-1 Receptor and Aprepitant In Melanomas M Muñ Oz Et Almentioning

confidence: 99%

“…Until now, this drug has been used as an antidepressant, anxiolytic and antiemetic. [27][28][29] Despite this, we have recently reported that aprepitant is a broad-spectrum antitumor drug. 30 However, to our knowledge, the presence of NK-1 receptors in melanomas and whether the antitumor action of the NK-1 receptor antagonist aprepitant is exerted on human malignant melanomas are unknown.…”

mentioning

confidence: 99%

The NK-1 receptor is expressed in human melanoma and is involved in the antitumor action of the NK-1 receptor antagonist aprepitant on melanoma cell lines

Muñoz

Rosso

Robles‐Frías

et al. 2010

Laboratory Investigation

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Melanoma, the most deadly form of skin cancer, is aggressive and resistant to current therapies. It has been previously reported that the substance P and neurokinin-1 (NK-1) receptor antagonists induce cell proliferation and cell inhibition, respectively, in human melanoma cell lines. Aprepitant is a selective high-affinity antagonist of the human NK-1 receptor. Until now, this drug has been used as an anxiolytic, antidepressant and antiemetic. Moreover, the antitumor action of aprepitant has been previously reported. However, the presence of NK-1 receptors in human melanomas and whether the antitumor action of the NK-1 receptor antagonist aprepitant is exerted on human malignant melanomas have not been previously described. The aims of this study are to show the presence of NK-1 receptors in human malignant melanomas and the antitumoral action of aprepitant against several human melanoma cell lines. Immunoblot analysis was used to determine the presence of NK-1 receptors in human melanoma cell lines, and immunohistochemistry was used to demonstrate NK-1 receptors in human melanoma samples. We performed an in vitro study of the cytotoxicity of the NK-1 receptor antagonist aprepitant on human melanoma cell lines. A coulter counter was used to determine viable cell numbers, followed by application of the tetrazolium compound MTS. The DAPI method was applied to demonstrate apoptosis. We observed that NK-1 receptors were present in all the melanoma samples studied as well as in human melanoma cell lines. We also showed that melanoma cell lines expressed mRNA for the NK-1 receptor. Moreover, after using a knockdown method, we showed that NK-1 receptors are involved in the viability of tumor cells. In this study, we also report that aprepitant, at 10-60 mM concentrations, elicits cell growth inhibition in a concentration-dependent manner in all melanoma cell lines studied, that the specific antitumor action of aprepitant occurs through the NK-1 receptor and that melanoma cell death is due to apoptosis. These findings show for the first time that the NK-1 receptor may be a promising new target and that the NK-1 receptor antagonist aprepitant could be a candidate as a new antitumor drug in the treatment of human melanoma.

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“…Involvement of substance P and NK 1 has been suggested in the generation of delayed emesis following the treatment with chemotherapeutic agents (20). Recent studies further demonstrated the suppression of delayed emesis by aprepitant in both humans and animals (4,5,10), although brain-nonpenetrating NK 1 antagonists are ineffective (21). Cisplatin induced long-lasting emesis in ferrets for 72 h. T-2328 inhibited the cisplatin-induced delayed emesis by i.v.…”

Section: Gr73632-induced Foot Tapping In Gerbilsmentioning

confidence: 99%

Pharmacological Characterization of T-2328, 2-Fluoro-4'-methoxy-3'-[[[(2S,3S)-2-phenyl-3-piperidinyl]amino]methyl]-[1,1'-biphenyl]-4-carbonitrile Dihydrochloride, as a Brain-Penetrating Antagonist of Tachykinin NK1 Receptor

Watanabe¹,

Asai²,

Ishii³

et al. 2008

J Pharmacol Sci

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Abstract. The pharmacological properties of T-2328 were evaluated as an antagonist of the tachykinin neurokinin 1 (NK 1 ) receptor. T-2328 inhibited the specific binding of [ 3 H][Sar 9 ,Met(O 2 ) 11 ]substance P to tachykinin NK 1 receptors in human lymphoblastic IM9 cells with K i of 0.08 nM. In the same assay, K i for aprepitant, a brain-penetrating NK 1 antagonist, was 1.3 nM. The antagonism of T-2328 is highly selective for the human NK 1 receptors since the affinities for human NK 2 , NK 3 receptors, and 13 other kinds of receptors and ion channels were >1000-fold lower than for NK 1 receptors. Reduction in Bmax with no change in affinity suggests the non-competitive nature of T-2328 interaction with the NK 1 receptor. T-2328 (0.03 -0.1 mg / kg, i.v.) and aprepitant (1 -3 mg / kg, i.v.) significantly prevented the GR73632 (i.c.v.)-induced foot tapping response in gerbils. The potencies of T-2328 in both in vitro and in vivo studies were more than 10 times greater than those of aprepitant. I.v. administration of T-2328 (0.1 -0.3 mg/ kg) potently blocked both acute and delayed emetic responses induced by cisplatin (5 mg / kg, i.p.) in ferrets. It is concluded that T-2328 is a potent, centrally active NK 1 antagonist. T-2328 may have potential as a novel therapeutic agent for the treatment of chemotherapyinduced emesis.

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The novel NK1 receptor antagonist MK–0869 (L–754,030) and its water soluble phosphoryl prodrug, L–758,298, inhibit acute and delayed cisplatin-induced emesis in ferrets

Cited by 128 publications

References 35 publications

Therapeutic Innovations for Targeting Hepatoblastoma

Therapeutic Innovations for Targeting Hepatoblastoma

The NK-1 receptor is expressed in human melanoma and is involved in the antitumor action of the NK-1 receptor antagonist aprepitant on melanoma cell lines

Pharmacological Characterization of T-2328, 2-Fluoro-4'-methoxy-3'-[[[(2S,3S)-2-phenyl-3-piperidinyl]amino]methyl]-[1,1'-biphenyl]-4-carbonitrile Dihydrochloride, as a Brain-Penetrating Antagonist of Tachykinin NK1 Receptor

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