N-[(R,R)-(E)-1-(4-chloro-benzyl)-3-(2-oxo-azepan-3-ylcarbamoyl)-allyl]-N-methyl-3,5-bis-trifluoromethyl-benzamide: an orally active neurokinin NK1/NK2 antagonist

Gerspacher, Marc; Sprecher, Andreas von; Mah, Robert; Anderson, Gary P.; Bertrand, Claude; Subramanian, N.; Hauser, Kathleen; Ball, Howard

doi:10.1016/s0960-894x(00)00260-2

Cited by 11 publications

(1 citation statement)

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“…, 1997) inhibits airway bronchoconstriction induced by SP, NKA and capsaicin and mucosal plasma extravasation produced by exogenous and endogenous release of tachykinins in guinea‐pig. A dual tachykinin NK 1 ‐ and NK 2 ‐receptor antagonist derived originally from the selective NK 1 ‐receptor antagonist CGP49823, exhibited a protective effect against the tachykinin NK 1 ‐receptor agonist sar 9 ‐SP‐ and β ‐Ala 8 ‐NKA‐induced bronchoconstriction in guinea‐pigs after oral administration (Gerspacher et al. , 2000).…”

Section: Discussionmentioning

confidence: 99%

Increased blocking activity of combined tachykinin NK₁‐ and NK₂‐receptor antagonists on tachykinergic bronchomotor responses in the guinea‐pig

Corboz¹,

Fernandez²,

Rizzo³

et al. 2003

Auton Autocoid Pharmacol

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1. The present study compared the effect of the administration of tachykinin NK1- and NK2-receptor antagonists alone and in combination on exogenous and endogenous tachykinin-induced contractions using three different guinea-pig airway preparations: isolated bronchus, isolated perfused lung and in vivo. 2. In the isolated bronchi, the tachykinin NK1-receptor antagonist CP 99994 (0.01-1 microM) produced concentration-dependent inhibition of contractions induced the tachykinin NK1-receptor agonists substance P (SP) and [Met-OMe11] SP ([Met-OMe11]SP), whereas the tachykinin NK2-receptor antagonist SR 48968 (0.1 microM) had no effect. SR 48968 (0.001-0.01 microM) concentration-dependently inhibited contractions induced by the tachykinin NK2-receptor agonists neurokinin A (NKA) and [beta-Ala8]-neurokinin A (4-10) ([betaAla8]-NKA) whereas CP 99994 (0.1 microM) did not inhibit the contractions. The contractile activity of capsaicin, an agent that releases endogenous tachykinins from sensory C-fibres, was inhibited in a concentration dependent manner by SR 48968 (0.001-0.03 microM) but not by CP 99994 (0.1 microM). Combination of CP 99994 and SR 48968 caused increased inhibitory effects on the concentration-response curves to SP, [Met-OMe1l]SP, NKA, [beta-Ala8]-NKA and capsaicin. 3. In isolated perfused lungs, SR 48968 concentration (0.01-10 microM) dependently inhibited NKA-, [beta-Ala8]-NKA- and capsaicin-induced bronchoconstriction whereas CP 99994 (30 microM) had no effect on SP-, NKA-, [beta-Ala8]-NKA- and capsaicin-induced bronchoconstriction. Combination of inactive concentrations of CP 99994 and SR 48968 produced an increased inhibitory effect on all previous stimuli-induced bronchoconstriction. 4. In in vivo guinea-pig studies, intravenous and oral pretreatment with SR 48968 (0.01-1 mg kg(-1) i.v. and 0.1-3 mg kg(-1) p.o., respectively), but not with CP 99994 (1 mg kg(-1) i.v. and 0.3-30 mg kg(-1) p.o., respectively), produced a dose-dependent inhibition of the bronchoconstrictor responses induced by NKA, [beta-Ala8]-NKA and capsaicin. CP 99994 intravenously (0.3 mg kg(-1)) and orally (3-10 mg kg(-1)) inhibited SP-induced bronchoconstriction only. Intravenous and oral low dose combinations of CP 99994 and SR 48968 produced an increased inhibition of SP-, NKA-, [beta-Ala8]-NKA- and capsaicin-induced bronchoconstriction, respectively. The present data indicate that combined tachykinin NK1- and NK2-receptor antagonist treatment compared with single antagonist treatment, using CP 99994 and SR 48968, produced an augmented blockade of tachykinin NK1-, NK2- and capsaicin-mediated contractions in guinea pig airways. These findings support the hypothesis that a dual NK1- and NK2-receptor antagonist may provide an advantage over single activity tachykinin NK1- or NK2-receptor antagonists in pulmonary obstructive diseases.

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Section: Discussionmentioning

confidence: 99%

Increased blocking activity of combined tachykinin NK₁‐ and NK₂‐receptor antagonists on tachykinergic bronchomotor responses in the guinea‐pig

Corboz¹,

Fernandez²,

Rizzo³

et al. 2003

Auton Autocoid Pharmacol

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ChemInform Abstract: N‐[(R,R)‐(E)‐1‐(4‐Chloro‐benzyl)‐3‐(2‐oxo‐azepan‐3‐ylcarbamoyl)‐allyl] ‐N‐methyl‐3,5‐bis‐trifluoromethyl‐benzamide: An Orally Active Neurokinin NK₁/NK₂ Antagonist.

et al. 2000

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Combined Tachykinin NK1, NK2, and NK3 Receptor Antagonists

Rumsey

Kerns

2004

Handbook of Experimental Pharmacology

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N-[(R,R)-(E)-1-(4-chloro-benzyl)-3-(2-oxo-azepan-3-ylcarbamoyl)-allyl]-N-methyl-3,5-bis-trifluoromethyl-benzamide: an orally active neurokinin NK1/NK2 antagonist

Cited by 11 publications

References 4 publications

Increased blocking activity of combined tachykinin NK₁‐ and NK₂‐receptor antagonists on tachykinergic bronchomotor responses in the guinea‐pig

Increased blocking activity of combined tachykinin NK₁‐ and NK₂‐receptor antagonists on tachykinergic bronchomotor responses in the guinea‐pig

ChemInform Abstract: N‐[(R,R)‐(E)‐1‐(4‐Chloro‐benzyl)‐3‐(2‐oxo‐azepan‐3‐ylcarbamoyl)‐allyl] ‐N‐methyl‐3,5‐bis‐trifluoromethyl‐benzamide: An Orally Active Neurokinin NK₁/NK₂ Antagonist.

Combined Tachykinin NK1, NK2, and NK3 Receptor Antagonists

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N-[(R,R)-(E)-1-(4-chloro-benzyl)-3-(2-oxo-azepan-3-ylcarbamoyl)-allyl]-N-methyl-3,5-bis-trifluoromethyl-benzamide: an orally active neurokinin NK1/NK2 antagonist

Cited by 11 publications

References 4 publications

Increased blocking activity of combined tachykinin NK1‐ and NK2‐receptor antagonists on tachykinergic bronchomotor responses in the guinea‐pig

Increased blocking activity of combined tachykinin NK1‐ and NK2‐receptor antagonists on tachykinergic bronchomotor responses in the guinea‐pig

ChemInform Abstract: N‐[(R,R)‐(E)‐1‐(4‐Chloro‐benzyl)‐3‐(2‐oxo‐azepan‐3‐ylcarbamoyl)‐allyl] ‐N‐methyl‐3,5‐bis‐trifluoromethyl‐benzamide: An Orally Active Neurokinin NK1/NK2 Antagonist.

Combined Tachykinin NK1, NK2, and NK3 Receptor Antagonists

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Increased blocking activity of combined tachykinin NK₁‐ and NK₂‐receptor antagonists on tachykinergic bronchomotor responses in the guinea‐pig

Increased blocking activity of combined tachykinin NK₁‐ and NK₂‐receptor antagonists on tachykinergic bronchomotor responses in the guinea‐pig

ChemInform Abstract: N‐[(R,R)‐(E)‐1‐(4‐Chloro‐benzyl)‐3‐(2‐oxo‐azepan‐3‐ylcarbamoyl)‐allyl] ‐N‐methyl‐3,5‐bis‐trifluoromethyl‐benzamide: An Orally Active Neurokinin NK₁/NK₂ Antagonist.