In vitro and in vivo predictors of the anti-emetic activity of tachykinin NK1 receptor antagonists

Rupniak, N. M. J.; Tattersall, F.D.; Williams, Angela; Rycroft, W.; Carlson, Emma; Cascieri, Margaret A.; Sadowski, S.; Ber, Elżbieta; Hale, Jeffrey J.; Mills, Sander G.; MacCoss, Malcolm; Seward, Eileen M.; Huscroft, Ian T.; Owen, Simon N.; Swain, Christopher J.; Hill, R.G.; Hargreaves, Richard

doi:10.1016/s0014-2999(97)85415-5

Cited by 115 publications

(71 citation statements)

References 37 publications

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“…Following in-vitro testing, the NK1 antagonists were tested in the NK1 agonist-induced foot-tapping assay, used routinely to measure the ability of NK1 antagonists to cross the blood-brain barrier, bind to the gerbil NK1 receptor, and block the central actions of a NK1 agonist (Bristow and Young 1994;Rupniak and Williams 1994;Rupniak et al 1997). The five NK1 antagonists attenuated NK1 agonist-induced foot-tapping, albeit with differing potencies, confirming that these NK1 antagonists had oral bioavailability and brain penetration.…”

Section: Discussionmentioning

confidence: 96%

“…Briefly, pretreatment with CNS penetrant NK1 antagonists blocks the rhythmic hind foot-tapping produced when the selective NK1 receptor agonist, GR-73632 , is administered into the CNS via intracerebroventricular (icv) injection (Bristow and Young 1994;Rupniak and Williams 1994;Rupniak et al 1997).…”

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confidence: 99%

“…To this end, five selective NK1 antagonists, namely 694,060,994,721, were tested in the gerbil elevated plusmaze. These antagonists are representative of compounds that have been described in the NK1 preclinical and clinical literature (McLean et al 1993;Rupniak and Williams 1994;McLean et al 1996;Rupniak et al 1997;Kramer et al 1998). Specifically, we first assayed the receptor binding profile of these five NK1 antagonists at gerbil, rat, and human NK1 receptors, to confirm that these NK1 antagonists have reduced affinity at rat NK1 receptors.…”

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confidence: 99%

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The Gerbil Elevated Plus-maze II Anxiolytic-like Effects of Selective Neurokinin NK1 Receptor Antagonists

Varty¹

2002

Neuropsychopharmacology

106

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Neurokinin NK1 receptor antagonists may have therapeutic potential in the treatment of anxiety and depression. Species variants in the NK1 receptor result in reduced affinity 694,060,994,721 produced anxiolyticlike The tachykinin system, particularly the neurokinin NK1 receptor, may represent a new target for the treatment of a number of psychiatric disorders. Of greatest significance to the field, Kramer et al. (1998) described the anxiolytic and antidepressant effects of the NK1 antagonist, MK-869, in a 6-week clinical trial in patients diagnosed with co-morbid anxiety and depression. In the few studies that have assessed the anxiolytic-like and antidepressant-like effects of NK1 receptor antagonists in preclinical tests, results support the hypotheses that NK1 receptor blockade may have a role in the treatment of affective disorders. For example, the NK1 an-

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Section: Discussionmentioning

confidence: 96%

mentioning

confidence: 99%

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confidence: 99%

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The Gerbil Elevated Plus-maze II Anxiolytic-like Effects of Selective Neurokinin NK1 Receptor Antagonists

Varty¹

2002

Neuropsychopharmacology

106

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“…The antiemetic action of NK 1 receptor antagonists appears central because: 1) brain penetration is required for activity [49]; 2) central injection of CNS penetrant or non-penetrant NK 1 receptor antagonists prevents emesis produced by the peripheral administration of cisplatin [21,54]; and 3) there is strong correspondence in the rank order of potency between NK 1 receptor antagonists' ID 50 s for their antiemetic activity in ferrets, and their ability to suppress foot tappings in gerbils induced by centrally injected NK 1 receptor selective agonists [35,49,51]. These models have been used concomitantly as indices for CNS penetration, antagonist activity, and CNS-mediated antiemetic potential of NK 1 receptor antagonists.…”

Section: Introductionmentioning

confidence: 99%

Utilization of the least shrew as a rapid and selective screening model for the antiemetic potential and brain penetration of substance P and NK1 receptor antagonists

et al. 2008

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Substance P (SP) is thought to play a cardinal role in emesis via the activation of central tachykinin NK 1 receptors during the delayed phase of vomiting produced by chemotherapeutics. Although the existing supportive evidence is significant, due to lack of an appropriate animal model, the evidence is indirect. As yet, no study has confirmed that emesis produced by SP or a selective NK 1 receptor agonist is sensitive to brain penetrating antagonists of either NK 1 , NK 2 , or NK 3 receptors. The goals of this investigation were to demonstrate: 1) whether intraperitoneal (i.p.) administration of either SP, a brain penetrating (GR73632) or non-penetrating (e.g. SarMet -SP) NK 1 receptor agonist, an NK 2 receptor agonist (GR64349), or an NK 3 receptor agonist (Pro 7 -NKB), would induce vomiting and/or scratching in the least shrew (Cryptotis parva) in a dose-dependent manner; and whether these effects are sensitive to the above selective receptor antagonists; 2) whether an exogenous emetic dose of SP (50 mg/kg, i.p.) can penetrate into the shrew brain stem and frontal cortex; 3) whether GR73632 (2.5 mg/kg, i.p.)-induced activation of NK 1 receptors increases Fos-measured neuronal activity in the neurons of both brain stem emetic nuclei and the enteric nervous system of the gut; and 4) whether selective ablation of peripheral NK 1 receptors can affect emesis produced by GR73632. The results clearly demonstrated that while SP produced vomiting only, GR73632 caused both emesis and scratching behavior dose-dependently in shrews, and these effects were sensitive to NK 1 -, but not NK 2 -or NK 3 -receptor antagonists. Neither the selective, non-penetrating NK 1 receptor agonists, nor the selective NK 2 -or NK 3 -receptor agonists, caused a significant dose-dependent behavioral effect. An emetic dose of SP selectively and rapidly penetrated the brain stem but not the frontal cortex. Systemic GR73632 increased Fos expression in the enteric nerve plexi, the medial subnucleus of nucleus tractus solitarius, and the dorsal motor nucleus of the vagus, but not the area postrema. Ablation of peripheral NK 1 receptors attenuated the ability of GR73632 to induce a maximal frequency of emesis and shifted its percent animals vomiting dose-response curve to the right. The NK 1 -ablated shrews exhibited scratching behavior after systemic GR73632-injection. These results, for the first time, affirm a cardinal role for central NK 1 receptors in SP-induced vomiting, and a Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. facilitatory role for gastrointestinal NK 1 receptors. In addition, the...

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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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In vitro and in vivo predictors of the anti-emetic activity of tachykinin NK1 receptor antagonists

Cited by 115 publications

References 37 publications

The Gerbil Elevated Plus-maze II Anxiolytic-like Effects of Selective Neurokinin NK1 Receptor Antagonists

The Gerbil Elevated Plus-maze II Anxiolytic-like Effects of Selective Neurokinin NK1 Receptor Antagonists

Utilization of the least shrew as a rapid and selective screening model for the antiemetic potential and brain penetration of substance P and NK1 receptor antagonists

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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