2-Phenyl-4-quinolinecarboxamides:  A Novel Class of Potent and Selective Non-Peptide Competitive Antagonists for the Human Neurokinin-3 Receptor

Giardina, Giuseppe; Sarau, Henry M.; Farina, Carlo; Medhurst, Andrew D.; Grugni, Mario; Foley, James J.; Raveglia, Luca F.; Schmidt, Dulcie B.; Rigolio, Roberto; Vassallo, Marco; Vecchietti, Vittorio; Hay, Douglas W. P.

doi:10.1021/jm9602423

Cited by 47 publications

(37 citation statements)

References 28 publications

(38 reference statements)

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“…It is only relatively recently that potent and selective, nonpeptide NK-3R antagonists have been identified Oury-Donat et al, 1995;Giardina et al, 1996;Sarau et al, 1997). It is anticipated that these tool compounds will assist greatly in the elucidation of the potential pathophysiological roles of the NK-3Rs, for which there is currently limited information.…”

Section: Discussionmentioning

confidence: 99%

“…SB 235375 belongs to the class of nonpeptide NK-3R antagonists that are based on the 4-quinolinecarboxamide backbone (Giardina et al, 1996). Functional and binding studies indicate that SB 235375 is a high-affinity antagonist for the hNK-3R: pA 2 ϭ 7.9 for inhibition of NKB-induced calcium mobilization in HEK 293-NK-3R cells, and K i ϭ 2.2 nM for inhibition of 125 I-MePhe 7 -NKB binding to CHOhNK-3R cell membranes.…”

Section: Discussionmentioning

confidence: 99%

“…A key event in the NK-3R research area occurred in 1995 with the identification of the first potent and selective, nonpeptide NK-3R antagonist, SR 142,801 (Emonds-Alt et al, 1995;Oury-Donat et al, 1995). This was followed soon thereafter with the report of a novel chemical class of potent, competitive, and selective nonpeptide NK-3R antagonists, based on the 4-quinolinecarboxamide backbone (Giardina et al, 1996). Members of this class include SB 223412 (Sarau et al, 1997) and SB 222200 (Sarau et al, 2000).…”

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confidence: 99%

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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

Hay¹,

Giardina²,

Griswold³

et al. 2002

J Pharmacol Exp Ther

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In this report the in vitro and in vivo pharmacological and pharmacokinetic profile of (Ϫ)-(S)-N-(␣-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 125 I- [MePhe 7 ]-neurokinin B (NKB) binding to membranes of Chinese hamster ovary (CHO) cells expressing the hNK-3R (CHO-hNK-3R) with a K i ϭ 2.2 nM and antagonized competitively NKB-induced Ca 2ϩ mobilization in human embryonic kidney (HEK) 293 cells expressing the hNK-3R (HEK 293-hNK-3R) with a K b ϭ 12 nM. SB 235375 antagonized senktide (NK-3R)-induced contractions in rabbit isolated iris sphincter (pA 2 ϭ 8.1) and guinea pig ileal circular smooth muscles (pA 2 ϭ 8.3). SB 235375 was selective for the hNK-3R compared with hNK-1 (K i Ͼ 100,000 nM) and hNK-2 receptors (K i ϭ 209 nM), and was without effect, at 1 M, 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 (ED 50 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.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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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

Hay¹,

Giardina²,

Griswold³

et al. 2002

J Pharmacol Exp Ther

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“…Differentially substituted 4-quinoline caboxyamides have also been identified as TACR3 selective antagonists which displayed similar potency but increased TACR3 selectivity compared to osanetant 155 .…”

Section: Non-peptide Analoguesmentioning

confidence: 99%

Current and future applications of GnRH, kisspeptin and neurokinin B analogues

Millar

Newton

2013

Nat Rev Endocrinol

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Reproductive hormones impact on all stages of life from gamete production, fertilisation, fetal development and parturition, neonatal development and puberty through to adulthood and senescence.The reproductive hormone cascade has therefore been the target for the development of numerous drugs which modulate its activity at many levels. As the central regulator of the cascade, gonadotropinreleasing hormone (GnRH) agonists and antagonists have found extensive applications in treating a wide range of hormone-dependent deseases such as precocious puberty, prostate cancer, benign prostatic hyperplasia, endometriosis and uterine fibroids, as well as being an essential component of in vitro fertilisation (IVF) protocols. Recently-discovered neuroendocrine peptides, kisspeptin (KP) and neurokinin B (NKB), have also been identified as therapeutic targets and novel agonists and antagonists are being developed as modulators of the cascade upstream of GnRH. Here we review the development and applications of analogues of the major neuroendocrine peptide regulators of the reproductive hormone cascade, GnRH, KP and NKB.

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“…Evidence from pharmacological studies using selective peptide hNK-3 receptor agonists revealed that the hNK-3 receptor exerts a neuromodulatory role in the central nervous system (CNS) and the periphery [16]. Among the family of hNK-3 receptor antagonists, the 2-phenylquinoline-4-carboxamide derivatives have been found to possess variable degrees of affinity towards the hNK-3 receptor [17].…”

Section: Introductionmentioning

confidence: 99%

Synthesis of 2‐(4‐Biphenylyl)quinoline‐4‐carboxylate and Carboxamide Analogs. New Human Neurokinin‐3 (hNK‐3) Receptor Antagonists

Saudi

Rostom

Fahmy

et al. 2003

Archiv der Pharmazie

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The 2-phenylquinoline-4-carboxamide 1 (Chart[TH]1) has been found to possess moderate affinity for human neurokinin-3 (hNK-3) receptor. In the present work, and in a trial to investigate the effect of the lipophilic moiety at C-2 of the quinoline ring on the antagonistic activity, an enlargement of the aromatic area at this position was suggested. In this respect, two series of 2-(4-biphenylyl)quinoline-4-carboxylates and carboxamides have been synthesized with certain modifications at the quinoline-2 and 4-position in order to study their effect on the anticipated hNK-3 receptor antagonistic activity. Fifteen compounds were screened for such activity using guinea-pig isolated ileum longitudinal muscle preparation and senktide as selective hNK-3 receptor agonist. Some compounds showed considerable antagonistic effect. Compound 7b, 6-bromo-2-(4-biphenylyl)quinoline-4-carboxylic acid, was the most prominent hNK-3 receptor antagonist in this study. Unexpectedly, some compounds were agonists.

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2-Phenyl-4-quinolinecarboxamides: A Novel Class of Potent and Selective Non-Peptide Competitive Antagonists for the Human Neurokinin-3 Receptor

Cited by 47 publications

References 28 publications

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

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

Current and future applications of GnRH, kisspeptin and neurokinin B analogues

Synthesis of 2‐(4‐Biphenylyl)quinoline‐4‐carboxylate and Carboxamide Analogs. New Human Neurokinin‐3 (hNK‐3) Receptor Antagonists

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