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Research ArticleCELLULAR AND MOLECULAR

Nonpeptide Tachykinin Receptor Antagonists. III. SB 235375, a Low Central Nervous System-Penetrant, Potent and Selective Neurokinin-3 Receptor Antagonist, Inhibits Citric Acid-Induced Cough and Airways Hyper-reactivity in Guinea Pigs

Douglas W. P. Hay, Giuseppe A. M. Giardina, Don E. Griswold, David C. Underwood, Charles J. Kotzer, Brian Bush, William Potts, Punam Sandhu, Dave Lundberg, James J. Foley, Dulcie B. Schmidt, Lenox D. Martin, David Kilian, Jeffrey J. Legos, Frank C. Barone, Mark A. Luttmann, Mario Grugni, Luca F. Raveglia and Henry M. Sarau
Journal of Pharmacology and Experimental Therapeutics January 2002, 300 (1) 314-323; DOI: https://doi.org/10.1124/jpet.300.1.314
Douglas W. P. Hay
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Giuseppe A. M. Giardina
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Don E. Griswold
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David C. Underwood
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Charles J. Kotzer
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Brian Bush
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William Potts
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Punam Sandhu
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Dave Lundberg
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James J. Foley
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Dulcie B. Schmidt
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Lenox D. Martin
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David Kilian
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Jeffrey J. Legos
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Mark A. Luttmann
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Mario Grugni
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Luca F. Raveglia
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Henry M. Sarau
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Abstract

In this report the in vitro and in vivo pharmacological and pharmacokinetic profile of (−)-(S)-N-(α-ethylbenzyl)-3-(carboxymethoxy)-2-phenylquinoline-4-carboxamide (SB 235375), a low central nervous system (CNS)-penetrant, human neurokinin-3 (NK-3) receptor (hNK-3R) antagonist, is described. SB 235375 inhibited 125I-[MePhe7]-neurokinin B (NKB) binding to membranes of Chinese hamster ovary (CHO) cells expressing the hNK-3R (CHO-hNK-3R) with aK i = 2.2 nM and antagonized competitively NKB-induced Ca2+ mobilization in human embryonic kidney (HEK) 293 cells expressing the hNK-3R (HEK 293-hNK-3R) with a K b = 12 nM. SB 235375 antagonized senktide (NK-3R)-induced contractions in rabbit isolated iris sphincter (pA2 = 8.1) and guinea pig ileal circular smooth muscles (pA2 = 8.3). SB 235375 was selective for the hNK-3R compared with hNK-1 (K i > 100,000 nM) and hNK-2 receptors (K i = 209 nM), and was without effect, at 1 μM, in 68 other receptor, enzyme, and ion channel assays. Intravenous SB 235375 produced a dose-related inhibition of miosis induced by i.v. senktide in the rabbit (ED50 of 0.56 mg/kg). Intraperitoneal SB 235375 (10–30 mg/kg) inhibited citric acid-induced cough and airways hyper-reactivity in guinea pigs. In mice oral SB 235375 (3–30 mg/kg) was without significant effect on the behavioral responses induced by intracerebral ventricular administration of senktide. Pharmacokinetic evaluation in the mouse and rat revealed that oral SB 235375 was well absorbed systemically but did not effectively cross the blood-brain barrier. The preclinical profile of SB 235375, encompassing high affinity, selectivity, oral activity, and low CNS penetration, suggests that it is an appropriate tool compound to define the pathophysiological roles of the NK-3Rs in the peripheral nervous system.

  • Abbreviations

    NKA
    neurokinin A
    NKB
    neurokinin B
    CNS
    central nervous system
    NK-1R
    neurokinin-1 receptor
    NK-2R
    neurokinin-2 receptor
    NK-3
    neurokinin-3
    NK-3R
    neurokinin-3 receptor
    PEG
    polyethylene glycol
    CHO
    Chinese hamster ovary
    CHO-hNK-3R
    CHO cells stably expressing the human NK-3R
    CHO-hNK-2R
    CHO cells stably expressing the human NK-2R
    CHO-hNK-1R
    CHO cells expressing the human NK-1R
    HEK
    human embryonic kidney
    HEK 293-hNK-3R
    HEK 293 cells stably expressing the human NK-3R
    HEK 293-mNK-3R
    HEK 293 cells transiently expressing the murine NK-3R
    HEK 293-mNK-2R
    HEK 293 cells transiently expressing the murine NK-2R
    IC50
    concentration of antagonist causing 50% inhibition of agonist response
    Ki
    apparent inhibition constant
    Kb
    dissociation constant
    ANOVA
    analysis of variance
    5-HT
    serotonin (5-hydroxytryptamine)
    • Received May 14, 2001.
    • Accepted September 27, 2001.
    • The American Society for Pharmacology and Experimental Therapeutics
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    Journal of Pharmacology and Experimental Therapeutics: 300 (1)
    Journal of Pharmacology and Experimental Therapeutics
    Vol. 300, Issue 1
    1 Jan 2002
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    Nonpeptide Tachykinin Receptor Antagonists. III. SB 235375, a Low Central Nervous System-Penetrant, Potent and Selective Neurokinin-3 Receptor Antagonist, Inhibits Citric Acid-Induced Cough and Airways Hyper-reactivity in Guinea Pigs
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    Citation Tools
    Research ArticleCELLULAR AND MOLECULAR

    Nonpeptide Tachykinin Receptor Antagonists. III. SB 235375, a Low Central Nervous System-Penetrant, Potent and Selective Neurokinin-3 Receptor Antagonist, Inhibits Citric Acid-Induced Cough and Airways Hyper-reactivity in Guinea Pigs

    Douglas W. P. Hay, Giuseppe A. M. Giardina, Don E. Griswold, David C. Underwood, Charles J. Kotzer, Brian Bush, William Potts, Punam Sandhu, Dave Lundberg, James J. Foley, Dulcie B. Schmidt, Lenox D. Martin, David Kilian, Jeffrey J. Legos, Frank C. Barone, Mark A. Luttmann, Mario Grugni, Luca F. Raveglia and Henry M. Sarau
    Journal of Pharmacology and Experimental Therapeutics January 1, 2002, 300 (1) 314-323; DOI: https://doi.org/10.1124/jpet.300.1.314

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    Research ArticleCELLULAR AND MOLECULAR

    Nonpeptide Tachykinin Receptor Antagonists. III. SB 235375, a Low Central Nervous System-Penetrant, Potent and Selective Neurokinin-3 Receptor Antagonist, Inhibits Citric Acid-Induced Cough and Airways Hyper-reactivity in Guinea Pigs

    Douglas W. P. Hay, Giuseppe A. M. Giardina, Don E. Griswold, David C. Underwood, Charles J. Kotzer, Brian Bush, William Potts, Punam Sandhu, Dave Lundberg, James J. Foley, Dulcie B. Schmidt, Lenox D. Martin, David Kilian, Jeffrey J. Legos, Frank C. Barone, Mark A. Luttmann, Mario Grugni, Luca F. Raveglia and Henry M. Sarau
    Journal of Pharmacology and Experimental Therapeutics January 1, 2002, 300 (1) 314-323; DOI: https://doi.org/10.1124/jpet.300.1.314
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