1.
2.
Bioorg Med Chem Lett
; 20(19): 5847-52, 2010 Oct 01.
Article
in English
| MEDLINE
| ID: mdl-20727752
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.
Subject(s)
Benzamides/chemistry , Receptors, Opioid, kappa/antagonists & inhibitors , Tropanes/chemistry , Animals , Benzamides/chemical synthesis , Benzamides/pharmacokinetics , Cell Line, Tumor , Diuresis/drug effects , Drug Evaluation, Preclinical , High-Throughput Screening Assays , Humans , Microsomes, Liver/metabolism , Rats , Receptors, Opioid, kappa/metabolism , Structure-Activity Relationship , Tropanes/chemical synthesis , Tropanes/pharmacokinetics
3.
4.
5.