MEN15596, a novel nonpeptide tachykinin NK2 receptor antagonist

Cialdai, Cecilia; Tramontana, Manuela; Patacchini, Riccardo; Lecci, Alessandro; Catalani, Claudio; Catalioto, Rose‐Marie; Meini, Stefania; Valenti, Claudio; Altamura, Maria Maddalena; Giuliani, Sandro; Maggi, Carlo Alberto

doi:10.1016/j.ejphar.2006.08.021

Cited by 27 publications

(41 citation statements)

References 24 publications

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“…In this context, utilization of the rabbit model would be reasonable to screen human-active NK 2 -R antagonists. Although in vivo antagonistic effects of NK 2 -R antagonists on colonic contractions have previously been demonstrated in rats and guinea pigs (12,18), there are no reports on their effects in rabbits. Therefore, we attempted to establish the agonist-induced colonic contrac- tion model in rabbits.…”

Section: Discussionmentioning

confidence: 99%

Establishment and Validation of a Rabbit Model for In Vivo Pharmacodynamic Screening of Tachykinin NK2 Antagonists

Tanaka¹,

Matsumoto-Okano²,

Inatomi³

et al. 2012

J Pharmacol Sci

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Abstract. We attempted to establish and validate an in vivo pharmacodynamic (PD) rabbit model to screen tachykinin NK 2 receptor (NK 2 -R) antagonists using pharmacological and pharmacokinetic (PK)/PD analyses. Under urethane anesthesia, changes in intracolonic pressure associated with intravenous (i.v.) administration of a selective NK 2 -R agonist, βAla 8 -neurokinin A(4-10) (βA-NKA), was monitored as a PD marker. The analgesic effects of NK 2 -R antagonists were evaluated by monitoring visceromotor response (VMR) to colorectal distension in a rabbit model of visceral hypersensitivity induced by intracolonic treatment of acetic acid. Intravenous administration of βA-NKA induced transient colonic contractions dose-dependently, which were inhibited by the selective NK 2 -R antagonists in dose-and/or plasma concentration-dependent manners. The correlation between PD inhibition and plasma concentration normalized with the corresponding in vitro binding affinity was relatively high (r 2 = 0.61). Furthermore, the minimum effective doses on the VMR and ID 50 values calculated in the PD model were highly correlated (r 2 = 0.74). In conclusion, we newly established and validated a rabbit model of agonist-induced colonic contractions as a screening tool for NK 2 -R antagonists. In a drug discovery process, this PD model could enhance the therapeutic candidate selection for irritable bowel syndrome, pharmacologically connecting in vitro affinity for NK 2 -R with in vivo therapeutic efficacy.

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Section: Discussionmentioning

confidence: 99%

Establishment and Validation of a Rabbit Model for In Vivo Pharmacodynamic Screening of Tachykinin NK2 Antagonists

Tanaka¹,

Matsumoto-Okano²,

Inatomi³

et al. 2012

J Pharmacol Sci

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“…5. C281Y (fourth extracellular loop) and I202F [TM4] were mutated as such because these mutations spontaneously occur in the rat tachykinin NK 2 R, and ibodutant displays low affinity for this species (Cialdai et al, 2006). C167G is a previously investigated mutation responsible for tachykinin Table 1.…”

Section: Resultsmentioning

confidence: 99%

“…Structure-activity studies, which led to the selection of this class of structures and then of ibodutant, have been disclosed recently (Fedi et al, 2007;Sisto et al, 2007;Porcelloni et al, 2008). The in vitro and in vivo pharmacological outlines of the nonpeptide antagonist ibodutant have indicated its high affinity and selectivity for the human tachykinin NK 2 R (pK i , 10.1) over the NK 1 (pK i , 6.1) and NK 3 (pK i , 6.4) subtypes and its antagonist potency in human (pK B , 9.2), guinea pig (pK B , 9.3), and minipig (pK B , 8.8) NK 2 R smooth muscle preparations (Cialdai et al, 2006). In the anesthetized guinea pigs, both after parenteral and oral administration, ibodutant potently blocks NK 2 R-mediated colonic motility and bronchoconstriction (Cialdai et al, 2006).…”

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Multifaceted Approach to Determine the Antagonist Molecular Mechanism and Interaction of Ibodutant ([1-(2-Phenyl-1R-{[1-(tetrahydropyran-4-ylmethyl)-piperidin-4-ylmethyl]-carbamoyl}-ethylcarbamoyl)-cyclopentyl]-amide) at the Human Tachykinin NK₂ Receptor

Meini

Bellucci²,

Catalani³

et al. 2009

J Pharmacol Exp Ther

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Ibodutant (MEN15596, [1-(2-phenyl-1R-{[1-(tetrahydropyran-4-ylmethyl)-piperidin-4-ylmethyl]-carbamoyl}-ethylcarbamoyl)-cyclopentyl]-amide) is a tachykinin NK. In functional experiments (phosphatidylinositol accumulation) in Chinese hamster ovary cells expressing the human NK 2 R, ibodutant potency measured toward concentration-response curves to neurokinin A as pK B was 10.6, and its antagonism mechanism was surmountable and competitive. In the same assay, antagonism equilibration and reversibility experiments of receptor blockade indicated that ibodutant quickly attains equilibrium and that reverts from receptor compartment in a slower manner. Kinetic properties of ibodutant were assessed through competitive binding kinetics experiments performed at [ 3 H]nepadutant and [ 3 H]saredutant binding sites. Determined K on and K off values indicated a fast association and slow dissociation rate of ibodutant at the different antagonist binding sites. Last, by radioligand binding experiments at some mutated human tachykinin NK 2 Rs, the amino acidic determinants crucial for the high affinity of ibodutant were identified at the transmembrane (TM) level: Cys167 in TM4; Ile202 and Tyr206 in TM5; Phe270, Tyr266, and Trp263 in TM6; and Tyr289 in TM7. These results indicated an extended antagonist binding pocket in the TM portion of the receptor, which is conceived crucial for TM3 and 6 arrangement and leads to G protein-coupled receptor activation. By combining this information and molecular modeling, the docking mode of ibodutant-human NK 2 R complex is proposed.G protein-coupled receptors (GPCRs) represent approximately 50% of current therapeutic targets. Antagonists for GPCR are so defined because of their capability to interfere with the ability of agonists in producing a given pharmacological response. The determination of the mechanism of action of an antagonist is one of the major pharmacological endeavors in drug discovery and can be helpful to predict the antagonist properties in the therapeutic situation.The tachykinin NK 2 receptor (NK 2 R) is a seven-transmembrane class A (rhodopsin-like) GPCR, which is preferentially activated by neurokinin A (NKA; HKTDSFVGLM-NH 2 ), leading to G q/11 coupling after activation of phospholipase C, thus producing inositol 3-phosphate and diacylglycerol (Almeida et al., 2004).

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“…Its unique chemical structure is completely different from that of other non-peptidic NK 2 -receptor antagonists (21,22). The remarkable complexity of the pharmacological characteristics of the tachykinin receptor has been documented based on past developments of selective tachykinin antagonists (10).…”

Section: Discussionmentioning

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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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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MEN15596, a novel nonpeptide tachykinin NK2 receptor antagonist

Cited by 27 publications

References 24 publications

Establishment and Validation of a Rabbit Model for In Vivo Pharmacodynamic Screening of Tachykinin NK2 Antagonists

Establishment and Validation of a Rabbit Model for In Vivo Pharmacodynamic Screening of Tachykinin NK2 Antagonists

Multifaceted Approach to Determine the Antagonist Molecular Mechanism and Interaction of Ibodutant ([1-(2-Phenyl-1R-{[1-(tetrahydropyran-4-ylmethyl)-piperidin-4-ylmethyl]-carbamoyl}-ethylcarbamoyl)-cyclopentyl]-amide) at the Human Tachykinin NK₂ Receptor

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

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MEN15596, a novel nonpeptide tachykinin NK2 receptor antagonist

Cited by 27 publications

References 24 publications

Establishment and Validation of a Rabbit Model for In Vivo Pharmacodynamic Screening of Tachykinin NK2 Antagonists

Establishment and Validation of a Rabbit Model for In Vivo Pharmacodynamic Screening of Tachykinin NK2 Antagonists

Multifaceted Approach to Determine the Antagonist Molecular Mechanism and Interaction of Ibodutant ([1-(2-Phenyl-1R-{[1-(tetrahydropyran-4-ylmethyl)-piperidin-4-ylmethyl]-carbamoyl}-ethylcarbamoyl)-cyclopentyl]-amide) at the Human Tachykinin NK2 Receptor

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

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About

Multifaceted Approach to Determine the Antagonist Molecular Mechanism and Interaction of Ibodutant ([1-(2-Phenyl-1R-{[1-(tetrahydropyran-4-ylmethyl)-piperidin-4-ylmethyl]-carbamoyl}-ethylcarbamoyl)-cyclopentyl]-amide) at the Human Tachykinin NK₂ Receptor