Abstract

The tachykinins, substance P, neurokinin A, and neurokinin B, have been implicated in many diseases. The present study evaluated the pharmacological properties of a novel tachykinin antagonist ZD6021 [3-cyano-N-((2S)-2-(3,4-dichlorophenyl)-4-[4-[2-(methyl-(S)-sulfinyl)-phenyl]piperidino]butyl)-N-methyl-]-napthamide]. The affinity (K_i) of ZD6021 for the cloned human neurokinin (NK)₁, NK₂, and NK₃ receptors was 0.12 ± 0.01, 0.64 ± 0.08, and 74 ± 13 nM, respectively. Mucin secretion by Chinese hamster ovary cells transfected with the human NK₁ receptor was dose dependently inhibited by ZD6021: pIC₅₀ = 7.6 ± 0.1. For NK₁ and NK₂ receptors, the agonist concentration-response curves using isolated tissues were displaced rightward in the presence of ZD6021: rabbit pulmonary artery, pA₂ = 8.7 and 8.5; human pulmonary artery and bronchus, pK_B = 8.9 ± 0.4 and 7.5 ± 0.2, at 10⁻⁷ M, respectively. Senktide-induced contractions of isolated guinea pig ileum were also blocked by low concentrations of ZD6021. Oral administration of ZD6021 to guinea pigs dose dependently attenuated tracheal extravasation of plasma proteins induced by the NK₁ receptor agonist Ac-[Arg⁶,Sar⁹,Met(O₂)¹¹]-SP(6-11), ED₅₀ = 0.8 μmol/kg, and bronchoconstriction, elicited by the NK₂ receptor agonist [β-Ala⁸]-NKA(4-10), ED₅₀ = 20 μmol/kg. Potency was unaffected by feeding. After oral administration of ZD6021, the time to peak activity was 150 min for the NK₁ receptor and 60 min for the NK₂ receptor with pharmacodynamic half-lives of 280 and 458 min, respectively. These data indicate that ZD6021 is a potent, orally active antagonist of all three tachykinin receptors. This compound may be useful for future studies of tachykinin-related pathology such as asthma.