title: The discovery of tropane derivatives as nociceptin receptor ligands for the management of cough and anxiety.
abstract: The discovery of 1 as a high-affinity ligand for the nociceptin receptor has led to the synthesis of a series of tropane (8-methyl-8-azabicyclo[3.2.1]octane) derivatives as optimized ligands. These compounds exhibit high affinity for the nociceptin receptor, moderate to excellent selectivity over the opioid mu receptor, and behave as full agonists. In this Letter, we present the synthesis and highlight the structure-activity relationship of tropane derivatives culminating in the identification of 24 and 32 as potent and orally active antitussive and anxiolytic agents. The in vitro and in vivo activities, pharmacokinetic profile, and the hPXR activity, which predicts the potential 3A4 induction in human, are disclosed.
authors.affiliation: Department of Chemical Research, CV & CNS, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Ginny D
authors.initials: GD
authors.lastname: Ho
authors.forename: John
authors.initials: J
authors.lastname: Anthes
authors.forename: Ana
authors.initials: A
authors.lastname: Bercovici
authors.forename: John P
authors.initials: JP
authors.lastname: Caldwell
authors.forename: Kuo-Chi
authors.initials: KC
authors.lastname: Cheng
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Cui
authors.forename: Ahmad
authors.initials: A
authors.lastname: Fawzi
authors.forename: Xiomara
authors.initials: X
authors.lastname: Fernandez
authors.forename: William J
authors.initials: WJ
authors.lastname: Greenlee
authors.forename: John
authors.initials: J
authors.lastname: Hey
authors.forename: Walter
authors.initials: W
authors.lastname: Korfmacher
authors.forename: Sherry X
authors.initials: SX
authors.lastname: Lu
authors.forename: Robbie L
authors.initials: RL
authors.lastname: McLeod
authors.forename: Fay
authors.initials: F
authors.lastname: Ng
authors.forename: April Smith
authors.initials: AS
authors.lastname: Torhan
authors.forename: Zheng
authors.initials: Z
authors.lastname: Tan
authors.forename: Deen
authors.initials: D
authors.lastname: Tulshian
authors.forename: Geoffrey B
authors.initials: GB
authors.lastname: Varty
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Xu
authors.forename: Hongtao
authors.initials: H
authors.lastname: Zhang