SCH 206272: a potent, orally active tachykinin NK1, NK2, and NK3 receptor antagonist

Anthes, John C.; Chapman, Richard W.; Richard, Christian; Eckel, Stephen; Corboz, Michel R.; Hey, John A.; Fernandez, Xiomara; Greenfeder, Scott; McLeod, Robbie L.; Sehring, Susan; Rizzo, Charles A.; Crawley, Yvette; Shih, Neng‐Yang; Piwinski, John J.; Reichard, Greg; Ting, Pauline C.; Carruthers, Nick; Cuss, Francis M.; Billah, M. Motasim; Kreutner, William; Egan, Robert W.

doi:10.1016/s0014-2999(02)02124-6

Cited by 37 publications

(11 citation statements)

References 33 publications

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“…Figure 1 and Table 1 (Table 1). We previously reported the tachykinin NK-receptor binding affinity of the standard tachykinin NK 3 -receptor antagonist SR 142801 [39]. SB 223412 is more selective for the tachykinin NK 3 receptors than SR 142801 in binding assays, confirming the study of Sarau et al [41].…”

Section: Discussionsupporting

confidence: 83%

Bronchoconstrictor effect of the tachykinin NK₃-receptor agonists [MePhe⁷]-neurokinin B and senktide in the isolated guinea pig lung

Corboz¹,

Rivelli²,

Eckel³

2010

Experimental Lung Research

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To determine whether bronchoconstriction can be mediated via the tachykinin NK₃ receptors, isolated guinea pig lungs were challenged with the exogenous tachykinin NK₃-receptor agonists [MePhe⁷]-neurokinin B ([MePhe⁷]-NKB) and senktide. [MePhe⁷]-NKB induced bronchoconstriction (EC50 = 11.8 ± 1.7 µM) that was significantly inhibited by the tachykinin NK₃-receptor antagonist SB 223412 at 10 µM (EC50 = 24.4 ± 4.5 µM). Senktide also induced bronchoconstriction (EC50 = 96.2 ± 20.3 µM) and the bronchoconstriction was significantly reduced by SB 223412 at 1 and 10 µM (EC50 = 270.8 ± 78.9 µM and 388.3 ± 105.5 µM, respectively). Although the authors demonstrated that SB 223412, [MePhe⁷]-NKB, and senktide are potent and selective for the tachykinin NK3 receptors in binding and functional (Ca(2+) mobilization) assays, the tachykinin NK₁-receptor antagonist CP 99,994 at 1 µM (EC50 = 32.7 ± 8.5 µM) produced inhibition of [MePhe⁷]-NKB-induced bronchoconstriction, whereas the tachykinin NK₂-receptor antagonist SR 48968 at 0.1 µM (EC50 = 213.2 ± 42.9 µM) blocked senktide-induced bronchoconstriction. These data suggest that [MePhe⁷]-NKB and senktide caused bronchoconstriction in guinea pig through activation of the tachykinin NK₃-receptors but the tachykinin NK₁- and/or NK₂-receptors are also involved in the response.

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Section: Discussionsupporting

confidence: 83%

Bronchoconstrictor effect of the tachykinin NK₃-receptor agonists [MePhe⁷]-neurokinin B and senktide in the isolated guinea pig lung

Corboz¹,

Rivelli²,

Eckel³

2010

Experimental Lung Research

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“…In this regard, NK-1R signaling by HK-1 is necessary for FcεRI-MC-dependent experimental chronic airway inflammation in mice [ 2 ]. However, specific NK-1R antagonists that inhibit allergen-induced bronchoconstriction and airway inflammation in rodents lack efficacy in the clinic [ 3 , 15 ]. These findings suggest that the failure of NK-1R antagonists in the clinic reflects the utilization of different GPCRs by SP and HK-1 in human versus murine MCs.…”

Section: Discussionmentioning

confidence: 99%

Upregulation of Mas-related G Protein coupled receptor X2 in asthmatic lung mast cells and its activation by the novel neuropeptide hemokinin-1

et al. 2018

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Hemokinin-1 (HK-1) is a novel neuropeptide produced by human bronchial cells and macrophages and causes contraction of human bronchi ex vivo. It is also generated by antigen/IgE-activated murine mast cells (MCs) and contributes to experimental chronic allergic airway inflammation via the activation of the neurokinin receptor-1 (NK-1R) expressed on murine MCs. We found elevated MC numbers in the lungs of individuals who died from asthma (asthma) when compared to lungs of individuals who died from other causes (non-asthma). Mas-related G Protein coupled receptor X2 (MRGPRX2) is a novel G-protein coupled receptor (GPCR) that is expressed predominantly on human MCs. We detected low level of MRGPRX2 in non-asthma lung MCs but its expression was significantly upregulated in asthma lung MCs. HK-1 caused degranulation in a human MC line (LAD2) and RBL-2H3 cells stably expressing MRGPRX2 and this response was resistant to inhibition by an NK-1R antagonist. However, knockdown of MRGPRX2 in LAD2 cells resulted in substantial inhibition of HK-1-induced degranulation. These findings suggest that while HK-1 contributes to the development of experimental asthma in mice via NK-1R on murine MCs the effect of this neuropeptide on human bronchoconstriction likely reflects the activation of MRGPRX2 on lung MCs. Thus, development of selective MRGPRX2 antagonists could serve as novel target for the modulation of asthma.

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“…, 2001). Also, a potent tachykinin NK 1 ‐, NK 2 ‐ and NK 3 ‐receptor antagonist SCH 206272, active across several species and a variety of in vitro and in vivo animal models, including humans, has been described (Anthes et al. , 2002).…”

Section: Discussionmentioning

confidence: 99%

Increased blocking activity of combined tachykinin NK₁‐ and NK₂‐receptor antagonists on tachykinergic bronchomotor responses in the guinea‐pig

Corboz¹,

Fernandez²,

Rizzo³

et al. 2003

Auton Autocoid Pharmacol

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1. The present study compared the effect of the administration of tachykinin NK1- and NK2-receptor antagonists alone and in combination on exogenous and endogenous tachykinin-induced contractions using three different guinea-pig airway preparations: isolated bronchus, isolated perfused lung and in vivo. 2. In the isolated bronchi, the tachykinin NK1-receptor antagonist CP 99994 (0.01-1 microM) produced concentration-dependent inhibition of contractions induced the tachykinin NK1-receptor agonists substance P (SP) and [Met-OMe11] SP ([Met-OMe11]SP), whereas the tachykinin NK2-receptor antagonist SR 48968 (0.1 microM) had no effect. SR 48968 (0.001-0.01 microM) concentration-dependently inhibited contractions induced by the tachykinin NK2-receptor agonists neurokinin A (NKA) and [beta-Ala8]-neurokinin A (4-10) ([betaAla8]-NKA) whereas CP 99994 (0.1 microM) did not inhibit the contractions. The contractile activity of capsaicin, an agent that releases endogenous tachykinins from sensory C-fibres, was inhibited in a concentration dependent manner by SR 48968 (0.001-0.03 microM) but not by CP 99994 (0.1 microM). Combination of CP 99994 and SR 48968 caused increased inhibitory effects on the concentration-response curves to SP, [Met-OMe1l]SP, NKA, [beta-Ala8]-NKA and capsaicin. 3. In isolated perfused lungs, SR 48968 concentration (0.01-10 microM) dependently inhibited NKA-, [beta-Ala8]-NKA- and capsaicin-induced bronchoconstriction whereas CP 99994 (30 microM) had no effect on SP-, NKA-, [beta-Ala8]-NKA- and capsaicin-induced bronchoconstriction. Combination of inactive concentrations of CP 99994 and SR 48968 produced an increased inhibitory effect on all previous stimuli-induced bronchoconstriction. 4. In in vivo guinea-pig studies, intravenous and oral pretreatment with SR 48968 (0.01-1 mg kg(-1) i.v. and 0.1-3 mg kg(-1) p.o., respectively), but not with CP 99994 (1 mg kg(-1) i.v. and 0.3-30 mg kg(-1) p.o., respectively), produced a dose-dependent inhibition of the bronchoconstrictor responses induced by NKA, [beta-Ala8]-NKA and capsaicin. CP 99994 intravenously (0.3 mg kg(-1)) and orally (3-10 mg kg(-1)) inhibited SP-induced bronchoconstriction only. Intravenous and oral low dose combinations of CP 99994 and SR 48968 produced an increased inhibition of SP-, NKA-, [beta-Ala8]-NKA- and capsaicin-induced bronchoconstriction, respectively. The present data indicate that combined tachykinin NK1- and NK2-receptor antagonist treatment compared with single antagonist treatment, using CP 99994 and SR 48968, produced an augmented blockade of tachykinin NK1-, NK2- and capsaicin-mediated contractions in guinea pig airways. These findings support the hypothesis that a dual NK1- and NK2-receptor antagonist may provide an advantage over single activity tachykinin NK1- or NK2-receptor antagonists in pulmonary obstructive diseases.

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SCH 206272: a potent, orally active tachykinin NK1, NK2, and NK3 receptor antagonist

Cited by 37 publications

References 33 publications

Bronchoconstrictor effect of the tachykinin NK₃-receptor agonists [MePhe⁷]-neurokinin B and senktide in the isolated guinea pig lung

Bronchoconstrictor effect of the tachykinin NK₃-receptor agonists [MePhe⁷]-neurokinin B and senktide in the isolated guinea pig lung

Upregulation of Mas-related G Protein coupled receptor X2 in asthmatic lung mast cells and its activation by the novel neuropeptide hemokinin-1

Increased blocking activity of combined tachykinin NK₁‐ and NK₂‐receptor antagonists on tachykinergic bronchomotor responses in the guinea‐pig

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SCH 206272: a potent, orally active tachykinin NK1, NK2, and NK3 receptor antagonist

Cited by 37 publications

References 33 publications

Bronchoconstrictor effect of the tachykinin NK3-receptor agonists [MePhe7]-neurokinin B and senktide in the isolated guinea pig lung

Bronchoconstrictor effect of the tachykinin NK3-receptor agonists [MePhe7]-neurokinin B and senktide in the isolated guinea pig lung

Upregulation of Mas-related G Protein coupled receptor X2 in asthmatic lung mast cells and its activation by the novel neuropeptide hemokinin-1

Increased blocking activity of combined tachykinin NK1‐ and NK2‐receptor antagonists on tachykinergic bronchomotor responses in the guinea‐pig

Contact Info

Product

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Bronchoconstrictor effect of the tachykinin NK₃-receptor agonists [MePhe⁷]-neurokinin B and senktide in the isolated guinea pig lung

Bronchoconstrictor effect of the tachykinin NK₃-receptor agonists [MePhe⁷]-neurokinin B and senktide in the isolated guinea pig lung

Increased blocking activity of combined tachykinin NK₁‐ and NK₂‐receptor antagonists on tachykinergic bronchomotor responses in the guinea‐pig