Pharmacological characterization of ZD6021: A novel, orally active antagonist of the tachykinin receptors

The tachykinins, substance P, neurokinin A, and neurokinin B, have been imp licated in many diseases. The present study evaluated the pharmacological p roperties of a novel tachykinin antagonist ZD6021 [3-cyano-N-((2S)-2-(3,4-d ichlorophenyl)-4-[4-[2-(methyl-(S)-sulfinyl)phenyl]piperidino]butyl)-N-meth yl-]-napthamide]. The affinity (K-i) of ZD6021 for the cloned human neuroki nin (NK)(1), NK2, and NK3 receptors was 0.12 +/- 0.01, 0.64 +/- 0.08, and 7 4 +/- 13 nM, respectively. Mucin secretion by Chinese hamster ovary cells t ransfected with the human NK1 receptor was dose dependently inhibited by ZD 6021: pIC(50) = 7.6 +/- 0.1. For NK1 and NK2 receptors, the agonist concent ration-response curves using isolated tissues were displaced rightward in t he presence of ZD6021: rabbit pulmonary artery, pA(2)= 8.7 and 8.5; human p ulmonary 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 ile um were also blocked by low concentrations of ZD6021. Oral administration o f ZD6021 to guinea pigs dose dependently attenuated tracheal extravasation of plasma proteins induced by the NK1 receptor agonist Ac-[Arg(6),Sar(9),Me t(O-2)(11)]-SP(6-11), ED50 = 0.8 mu mol/kg, and bronchoconstriction, elicit ed by the NK2 receptor agonist [beta -Ala(8)]-NKA(4-10), ED50 = 20 mu mol/k g. Potency was unaffected by feeding. After oral administration bf ZD6021, the time to peak activity was 150 min for the NK1 receptor and 60 min for t he NK2 receptor with pharmacodynamic half-lives of 280 and 458 min, respect ively. These data indicate that ZD6021 is a potent, orally active antagonis t of all three tachykinin receptors. This compound may be useful for future studies of tachykinin-related pathology such as asthma.