title: Pharmacological characterization of ZD6021: a novel, orally active antagonist of the tachykinin receptors.
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: pIC(50) = 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, 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 micromol/kg, and bronchoconstriction, elicited by the NK2 receptor agonist [beta-Ala8]-NKA(4-10), ED50 = 20 micromol/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.
authors.affiliation: AstraZeneca Pharmaceuticals Discovery Research, Wilmington, Delaware 19850, USA. Rumsey@AstraZeneca.com
authors.forename: W L
authors.initials: WL
authors.lastname: Rumsey
authors.forename: D
authors.initials: D
authors.lastname: Aharony
authors.forename: R A
authors.initials: RA
authors.lastname: Bialecki
authors.forename: B M
authors.initials: BM
authors.lastname: Abbott
authors.forename: H G
authors.initials: HG
authors.lastname: Barthlow
authors.forename: R
authors.initials: R
authors.lastname: Caccese
authors.forename: S
authors.initials: S
authors.lastname: Ghanekar
authors.forename: D
authors.initials: D
authors.lastname: Lengel
authors.forename: M
authors.initials: M
authors.lastname: McCarthy
authors.forename: B
authors.initials: B
authors.lastname: Wenrich
authors.forename: B
authors.initials: B
authors.lastname: Undem
authors.forename: C
authors.initials: C
authors.lastname: Ohnmacht
authors.forename: A
authors.initials: A
authors.lastname: Shenvi
authors.forename: J S
authors.initials: JS
authors.lastname: Albert
authors.forename: F
authors.initials: F
authors.lastname: Brown
authors.forename: P R
authors.initials: PR
authors.lastname: Bernstein
authors.forename: K
authors.initials: K
authors.lastname: Russell
mesh_terms: D000284:Administration, Oral; D000818:Animals; D016084:Bronchoconstriction / Q000187:drug effects*; D006224:Cricetinae; D006168:Guinea Pigs; D006801:Humans; D007082:Ileum / Q000187:drug effects* / Q000502:physiology; D008297:Male; D064729:Neurokinin-1 Receptor Antagonists; D010446:Peptide Fragments / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011651:Pulmonary Artery / Q000187:drug effects* / Q000502:physiology; D011817:Rabbits; D018040:Receptors, Neurokinin-1 / Q000378:metabolism; D018041:Receptors, Neurokinin-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018042:Receptors, Neurokinin-3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018039:Receptors, Tachykinin / Q000037:antagonists & inhibitors / Q000378:metabolism; D013373:Substance P / Q000031:analogs & derivatives* / Q000494:pharmacology; D013454:Sulfoxides / Q000494:pharmacology
chemical_list: D064729:Neurokinin-1 Receptor Antagonists; D010446:Peptide Fragments; D010880:Piperidines; D018040:Receptors, Neurokinin-1; D018041:Receptors, Neurokinin-2; D018042:Receptors, Neurokinin-3; D018039:Receptors, Tachykinin; D013454:Sulfoxides; C430919:ZD 6021; C054724:senktide; D013373:Substance P