2. Academic Validation
  3. SCH 206272: a potent, orally active tachykinin NK(1), NK(2), and NK(3) receptor antagonist

SCH 206272: a potent, orally active tachykinin NK(1), NK(2), and NK(3) receptor antagonist

  • Eur J Pharmacol. 2002 Aug 23;450(2):191-202. doi: 10.1016/s0014-2999(02)02124-6.
John C Anthes 1,  Richard W Chapman,  Christian Richard,  Stephen Eckel,  Michel Corboz,  John A Hey,  Xiomara Fernandez,  Scott Greenfeder,  Robbie McLeod,  Susan Sehring,  Charles Rizzo,  Yvette Crawley,  Neng-Yang Shih,  John Piwinski,  Greg Reichard,  Pauline Ting,  Nick Carruthers,  Francis M Cuss,  Motasim Billah,  William Kreutner,  Robert W Egan
Affiliations

Affiliation

  • 1 Department of Allergy, Schering-Plough Research Institute, K15-1-1600, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA. john.anthes@spcorp.com
PMID: 12206858 DOI: 10.1016/s0014-2999(02)02124-6
Abstract

Experiments were performed to characterize the pharmacology of SCH 206272 [(R,R)-1'[5-[(3,5-dichlorobenzoyl)methylamino]-3-(3,4-dichlorophenyl)-4(Z)-(methoxyimino)pentyl]-N-methyl-2-oxo-[1,4'bipiperidine]-3-acetamide] as a potent and selective antagonist of tachykinin (NK) NK(1), NK(2), and NK(3) receptors. SCH 206272 inhibited binding at human tachykinin NK(1), NK(2), and NK(3) receptors (K(i) = 1.3, 0.4, and 0.3 nM, respectively) and antagonized [CA(2+)](i) mobilization in Chinese hamster ovary (CHO) cells expressing the cloned human tachykinin NK(1), NK(2), or NK(3) receptors. SCH 206272 inhibited relaxation of the human pulmonary artery (pK(b) = 7.7 +/- 0.3) induced by the tachykinin NK(1) receptor agonist, [Met-O-Me] substance P and contraction of the human bronchus (pK(b = 8.2 +/- 0.3) induced by the tachykinin NK(2) receptor agonist, neurokinin A. In isolated guinea pig tissues, SCH 206272 inhibited substance P-induced enhancement of electrical field stimulated contractions of the vas deferens, (pK(b = 7.6 +/- 0.2), NKA-induced contraction of the bronchus (pK(b) = 7.7 +/- 0.2), and senktide-induced contraction of the ileum. In vivo, oral SCH 206272 (0.1-10 mg/kg, p.o.) inhibited substance P-induced airway microvascular leakage and neurokinin A-induced bronchospasm in the guinea pig. In a canine in vivo model, SCH 206272 (0.1-3 mg/kg, p.o.) inhibited NK(1) and NK(2) activities induced by exogenous substance P and neurokinin A. Furthermore, in guinea pig models involving endogenously released tachykinins, SCH 206272 inhibited hyperventilation-induced bronchospasm, capsaicin-induced cough, and airway microvascular leakage induced by nebulized hypertonic saline. These data demonstrate that SCH 206272 is a potent, orally active tachykinin NK(1), NK(2), and NK(3) receptor antagonist. This compound may have beneficial effects in diseases thought to be mediated by tachykinins, such as cough, asthma, and chronic obstructive pulmonary disease.

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