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

William L. Rumsey, David Aharony, Russell A. Bialecki, Brian M. Abbott, Herbert G. Barthlow, Robert Caccese, Smita Ghanekar, David Lengel, Michelle Mccarthy, Barbara Wenrich, Bradley Undem, Cyrus Ohnmacht, Ashok Shenvi, Jeffrey S. Albert, Fred Brown, Peter R. Bernstein, Keith Russell

Research output: Contribution to journalArticlepeer-review


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 (Ki) 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: plC50 = 7.6 ± 0.1. For NK1 and NK2 receptors, the agonist concentration-response curves using isolated tissues were displaced right-ward in the presence of ZD6021: rabbit pulmonary artery, pA2 = 8.7 and 8.5; human pulmonary artery and bronchus, pKB = 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.

Original languageEnglish (US)
Pages (from-to)307-315
Number of pages9
JournalJournal of Pharmacology and Experimental Therapeutics
Issue number1
StatePublished - 2001

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology


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