title: Discovery of 8-azabicyclo[3.2.1]octan-3-yloxy-benzamides as selective antagonists of the kappa opioid receptor. Part 1.
abstract: Initial high throughput screening efforts identified highly potent and selective kappa opioid receptor antagonist 3 (κ IC(50)=77 nM; μ:κ and δ:κ IC(50) ratios>400) which lacked CNS exposure in vivo. Modification of this scaffold resulted in development of a series of 8-azabicyclo[3.2.1]octan-3-yloxy-benzamides showing potent and selectivity κ antagonism as well as good brain exposure. Analog 6c (κ IC(50)=20 nM; μ:κ=36, δ:κ=415) was also shown to reverse κ-agonist induced rat diuresis in vivo.
authors: CNS Discovery Research, AstraZeneca Pharmaceuticals, 1800 Concord Pike, Wilmington, DE 19850, USA.
authors: Todd A
authors: TA
authors: Brugel
authors: Reed W
authors: RW
authors: Smith
authors: Michael
authors: M
authors: Balestra
authors: Christopher
authors: C
authors: Becker
authors: Thalia
authors: T
authors: Daniels
authors: Tiffany N
authors: TN
authors: Hoerter
authors: Gerard M
authors: GM
authors: Koether
authors: Scott R
authors: SR
authors: Throner
authors: Laura M
authors: LM
authors: Panko
authors: James J
authors: JJ
authors: Folmer
authors: Joseph
authors: J
authors: Cacciola
authors: Angela M
authors: AM
authors: Hunter
authors: Ruifeng
authors: R
authors: Liu
authors: Philip D
authors: PD
authors: Edwards
authors: Dean G
authors: DG
authors: Brown
authors: John
authors: J
authors: Gordon
authors: Norman C
authors: NC
authors: Ledonne
authors: Mark
authors: M
authors: Pietras
authors: Patricia
authors: P
authors: Schroeder
authors: Linda A
authors: LA
authors: Sygowski
authors: Lee T
authors: LT
authors: Hirata
authors: Anna
authors: A
authors: Zacco
authors: Matthew F
authors: MF
authors: Peters
mesh_terms: D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D004231:Diuresis / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D057166:High-Throughput Screening Assays; D006801:Humans; D008862:Microsomes, Liver / Q000378:metabolism; D051381:Rats; D017473:Receptors, Opioid, kappa / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014326:Tropanes / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics
chemical_list: D001549:Benzamides; D017473:Receptors, Opioid, kappa; D014326:Tropanes