Publication Details (including relevant citation information):
Bioorg Med Chem Lett. 2010 Oct 1;20(19):5847-52. doi: 10.1016/j.bmcl.2010.07.113. Epub 2010 Jul 30.
Discovery of 8-azabicyclo[3.2.1]octan-3-yloxy-benzamides as selective antagonists of the kappa opioid receptor. Part 1.
Brugel TA, Smith RW, Balestra M, Becker C, Daniels T, Hoerter TN, Koether GM, Throner SR, Panko LM, Folmer JJ, Cacciola J, Hunter AM, Liu R, Edwards PD,Brown DG, Gordon J, Ledonne NC, Pietras M, Schroeder P, Sygowski LA, Hirata LT, Zacco A, Peters MF.
CNS Discovery Research, AstraZeneca Pharmaceuticals, 1800 Concord Pike, Wilmington, DE 19850, USA.
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.