Dual neurokinin NK1/NK2 receptor antagonists

Gerspacher, Marc; Sprecher, Andreas von

doi:10.1358/dof.1999.024.08.858627

Cited by 18 publications

(10 citation statements)

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“…Several reviews on NK 1 antagonists have recently appeared [193][194][195][196]60]. An exploratory study on tachykinin antagonists was initiated by Folkers'group [197], who first reported the synthesis of SP antagonists [198], followed by Escher [69] and others [199].…”

Section: Peptide Derived Antagonistsmentioning

confidence: 99%

Substance P: Structure, Function, and Therapeutics

Datar

Srivastava²,

Coutinho³

et al. 2004

CTMC

148

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Extensive efforts since 1931, on the structural determination of the mammalian tachykinin SP by NMR, CD and IR have turned out to be inconclusive. Studies are now being concentrated on the structural properties and characteristics of various NK receptors (NK(1), NK(2) and NK(3)) with the help of genetics, cloning, receptor engineering, mutagenesis and modeling. This knowledge is now being fruitfully used in the development of non-peptide NK(1) receptor antagonists that essentially block the pharmacological effects of SP. It is now being realized that the simultaneous blockade of two or more receptors gives promising results in emesis, depression and pulmonary obstructive diseases. In addition to the synthetic compounds, the discovery of antagonists from natural origin has added a great value to this field. In this review we have made an attempt to present the structural characteristics of SP, its analogs and antagonists, the structural characteristics of the NK receptor, and structure activity relationships that have helped to improve the therapeutic utilities of SP antagonists.

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Section: Peptide Derived Antagonistsmentioning

confidence: 99%

Substance P: Structure, Function, and Therapeutics

Datar

Srivastava²,

Coutinho³

et al. 2004

CTMC

148

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“…NK 1 and NK 2 are widely distributed in the central nervous system (CNS) and peripheral tissue, and NK 3 appears to be more localized in the CNS . Functioning as neurotransmitters or neuromodulatory agents, SP, NKA, and NKB may be involved in several pathophysiological conditions including asthma, arthritis, cough, emesis, anxiety, depression, pain, urinary incontinence, and inflammatory bowel disease. , The areas of neurokinin antagonist development have been extensively reviewed. − …”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, and SAR of Tachykinin Antagonists: Modulation of Balance in NK₁/NK₂ Receptor Antagonist Activity

et al. 2002

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Through optimization of compounds based on the dual NK(1)/NK(2) antagonist ZD6021, it was found that alteration of two key regions could modulate the balance of NK(1) and NK(2) potency. Substitution of the 2-naphthalene position in analogues of ZD6021 resulted in increased NK(1) potency and thus afforded NK(1) preferential antagonists. Alterations of the piperidine region could then increase NK(2) potency to restore dual NK(1)/NK(2) selectivity. Through these efforts, three novel receptor antagonists from a single chemically related series were identified; two are dual NK(1)/NK(2) antagonists, and the third is an NK(1) preferential antagonist. In this paper, the factors affecting the balance of NK(1) and NK(2) selectivity in this series are discussed and the in vitro and in vivo properties of the novel antagonists are described.

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“…There is now evidence that tachykinins are involved in a number of diseases and after the search for selective tachykinin antagonists, several pharmaceutical companies shifted their effort from selective towards the discovery of non-peptidic compounds exhibiting dual NK 1 /NK 2 antagonist properties [19]. Indeed, compounds such as YM-44778 exhibit this profile and could be useful for the understanding of the pathological roles of the tachykinin receptor subtypes involved.…”

Section: Discussionmentioning

confidence: 99%

Effect of YM-44781, YM-44778 and YM-49598, Novel Tachykinin Antagonists, in a Drug-Induced Bladder Contraction Model

Choppin¹,

Groke²,

Bringas³

et al. 2002

Pharmacology

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The radioligand binding profiles and in vivo pharmacological characteristics of YM-44781, YM-44778 and YM-49598, novel non-peptide tachykinin receptor antagonists, were examined and compared to those of FK-888 and GR-159897. Since no functional NK₃ receptors were found in the rat bladder, the emphasis will be on the other two subtypes. YM-44781 and YM-49598 exhibited high binding affinities at NK₂ (pK_i = 9.94 ± 0.03) and NK₁ (pK_i = 9.09 ± 0.02) receptors, respectively, whereas YM-44778 exhibited high binding affinities at both NK₁ (pK_i = 8.08 ± 0.07) and NK₂ (pK_i = 8.55 + 0.04) receptors stably transfected in CHO-K1 cells (Chinese hamster ovary cells). In an in vivo rat model, a drug-induced bladder contraction model, antagonism of the contractions produced by the selective NK₂ receptor agonist, [βAla⁸]neurokinin A (4–10) (10 µg·kg^–1 i.v.) was observed after intravenous administration (dose range 0.001–1 mg·kg^–1) of YM-44781 and YM-44778 (IC₅₀ = 27 ± 8 and 100 ± 44 µg· kg^–1, respectively). YM-44781 was more potent (about 3-fold) than YM-44778. YM-49598 was almost inactive but produced a potent inhibition (IC₅₀ = 11 ± 7 µg·kg^–1) of the contraction of the rat urinary bladder induced by challenge with the NK₁-selective receptor agonist [Sar⁹,Met(O₂)¹¹]substance P sulphone (0.3 µg·kg^–1). YM-44781 and YM-44778 did not produce major inhibition of [Sar⁹,Met(O₂)¹¹]substance P-induced bladder contraction. These findings indicate that YM-44781 and YM-49598 are potent NK₂ and NK₁ receptor antagonists, respectively, whereas YM-44778 is a nonselective NK₂/NK₁ receptor antagonist in the drug-induced bladder contraction model.

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Dual neurokinin NK1/NK2 receptor antagonists

Cited by 18 publications

References 0 publications

Substance P: Structure, Function, and Therapeutics

Substance P: Structure, Function, and Therapeutics

Design, Synthesis, and SAR of Tachykinin Antagonists: Modulation of Balance in NK₁/NK₂ Receptor Antagonist Activity

Effect of YM-44781, YM-44778 and YM-49598, Novel Tachykinin Antagonists, in a Drug-Induced Bladder Contraction Model

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Dual neurokinin NK1/NK2 receptor antagonists

Cited by 18 publications

References 0 publications

Substance P: Structure, Function, and Therapeutics

Substance P: Structure, Function, and Therapeutics

Design, Synthesis, and SAR of Tachykinin Antagonists: Modulation of Balance in NK1/NK2 Receptor Antagonist Activity

Effect of YM-44781, YM-44778 and YM-49598, Novel Tachykinin Antagonists, in a Drug-Induced Bladder Contraction Model

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Design, Synthesis, and SAR of Tachykinin Antagonists: Modulation of Balance in NK₁/NK₂ Receptor Antagonist Activity