Biochemical and pharmacological activities of SR 144190, a new potent non-peptide tachykinin NK2 receptor antagonist

Emonds‐Alt, Xavier; Advenier, C.; Cognon, Cécile; Croci, Tiziano; Daoul, S; Ducoux, Jean-Philippe; Landi, Marco; Naline, Emmanuel; Néliat, Gervais; Poncelet, Marc; Proietto, Vincenzo; Broeck, Didier Van; Vilain, P.; Soubrié, Philippe; Fur, G. Le; Maffrand, Jean‐Pierre; Brelière, Jean-Claude

doi:10.1016/s0143-4179(97)90039-1

Cited by 44 publications

(19 citation statements)

References 31 publications

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“…In this model, TAK-480 significantly and dosedependently suppressed prompted defecation, suggesting an important role of the NK 2 receptor in enhanced defecation following mucosal stimulation by ricinoleic acid. In support of our finding, major involvement of the NK 2 receptor has been demonstrated in a rat model of castor oil-induced defecation in which endogenous tachykinins could account for enhanced gut motility and secretion (29,30). Another finding of this study was that the maximum potency of TAK-480 was equivalent to that of alosetron.…”

Section: Discussionsupporting

confidence: 88%

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Effects of TAK-480, a Novel Tachykinin NK2^|^ndash;Receptor Antagonist, on Visceral Hypersensitivity in Rabbits and Ricinoleic Acid^|^ndash;Induced Defecation in Guinea Pigs

Tanaka¹,

Tanaka²,

Nakamura³

et al. 2012

J Pharmacol Sci

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Abstract. TAK-480, 4-(difluoromethoxy)-N-((1R,2S)-2-(((3aR,4R,9bR)-4-(methoxymethyl)-2, 3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinolin-1-yl)carbonyl)cyclohexyl)benzamide, is a novel tachykinin NK 2 -receptor antagonist. In this study, we investigated its antagonistic activity and efficacy in animal models of visceral hypersensitivity and stimulated bowel function which have been implicated to underlie the symptoms in irritable bowel syndrome (IBS). TAK-480 showed potent binding affinity for human NK 2 receptors with a marked species difference and a 10,000-fold selectivity versus NK 1 and NK 3 receptors. TAK-480 dose-dependently antagonized colonic contractions induced by administration of the NK 2 receptor-selective agonist beta-Ala 8 -NKA(4-10) (βA-NKA) in anesthetized rabbits. In a rabbit model of intracolonic zymosan-induced visceral hypersensitivity, TAK-480 markedly inhibited the visceromotor response to colorectal distension, in contrast to the moderate inhibition by the serotonin 5-HT 3 -receptor antagonist alosetron. In addition, TAK-480 suppressed ricinoleic acid-induced defecation without affecting spontaneous defecation in guinea pigs, whereas alosetron suppressed both. Furthermore, TAK-480 inhibited smooth muscle contractions produced by natural tachykinins (substance P, neurokinin A, and neurokinin B) as well as βA-NKA in an isolated human colon. In conclusion, the novel NK 2 -receptor antagonist TAK-480 improved visceral hypersensitivity and accelerated defecation without causing constipation in experimental animals. Furthermore, the potent functional blockade of NK 2 receptors in human colon might suggest the potential effectiveness of TAK-480 in IBS patients.

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Section: Discussionsupporting

confidence: 88%

“…The homogenates were centrifuged at 2,000 rpm (Roter: R17A, Hitachi himac CR21G; Hitachi Koki Co., Ltd., Tokyo) for 10 min at 4°C. The supernatants were collected, suspended in suspension buffer, and centrifuged at 30 …”

Section: Tachykinin-receptor Binding Assaymentioning

confidence: 99%

Effects of TAK-480, a Novel Tachykinin NK2^|^ndash;Receptor Antagonist, on Visceral Hypersensitivity in Rabbits and Ricinoleic Acid^|^ndash;Induced Defecation in Guinea Pigs

Tanaka¹,

Tanaka²,

Nakamura³

et al. 2012

J Pharmacol Sci

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“…26,29,30 SR-140,333 and SR-144,190 were used at concentrations known to be effective and selective for NK 1 and NK 2 receptors, respectively, but devoid of any major influence on peristalsis on their own. 26,31 Atropine and hexamethonium, in contrast, caused a temporary peristaltic arrest which, as previously observed, [32][33][34] was released after some time, enabling us to test drug effects on noncholinergic propulsive motility. The findings that hexamethonium eliminated the properistaltic action of ET-1, whereas atropine, SR-140,333, and SR-144,190 were without effect, indicate that ET-1 stimulates peristalsis by an action on enteric neurons.…”

Section: Discussionmentioning

confidence: 64%

Regulation of Guinea pig intestinal peristalsis by endogenous endothelin acting at ETB receptors

Shahbazian

Holzer

2000

Gastroenterology

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“…This animal has been utilised extensively, with cough being induced in conscious animals by inhalation of aerosols of either capsaicin or low pH solutions such as citric acid [10,123,[127][128][129]. The guinea pig provides a good model of the human cough reflex, and this has been confirmed in a study showing the similarity in response to both citric acid and capsaicin in humans and the guinea pig [10].…”

Section: Speciesmentioning

confidence: 93%

ERS guidelines on the assessment of cough

Morice¹,

Fontana²,

Belvisi³

et al. 2007

Eur Respir J

613

619

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Biochemical and pharmacological activities of SR 144190, a new potent non-peptide tachykinin NK2 receptor antagonist

Cited by 44 publications

References 31 publications

Effects of TAK-480, a Novel Tachykinin NK2^|^ndash;Receptor Antagonist, on Visceral Hypersensitivity in Rabbits and Ricinoleic Acid^|^ndash;Induced Defecation in Guinea Pigs

Effects of TAK-480, a Novel Tachykinin NK2^|^ndash;Receptor Antagonist, on Visceral Hypersensitivity in Rabbits and Ricinoleic Acid^|^ndash;Induced Defecation in Guinea Pigs

Regulation of Guinea pig intestinal peristalsis by endogenous endothelin acting at ETB receptors

ERS guidelines on the assessment of cough

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