SCH 206272:: a potent, orally active tachykinin NK1, NK2, and NK3 receptor antagonist

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) NK1, NK2, and NK3 receptors. SCH 206272 inhibited binding at human tachykinin NK1, NK2, and NK3 receptors (K-i=1.3, 0.4, and 0.3 nM, respectively) and antagonized [Ca2+](i) mobilization in Chinese hamster ovary (CHO) cells expressing the cloned human tachykinin NK1, NK2, or NK3 receptors. SCH 206272 inhibited relaxation of the human pulmonary artery (pK(b) = 7.7 0.3) induced by the tachykinin NK1 receptor agonist, [Met-O-Me] substance P and contraction of the human bronchus (pK(b) = 8.2 0.3) induced by the tachykinin NK2 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 NK1 and NK2 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 NK1, NK2, and NK3 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. (C) 2002 Elsevier Science B.V. All rights reserved.