Discovery of 8-azabicyclo[3.2.1]octan-3-yloxy-benzamides as selective antagonists of the kappa opioid receptor. Part 1

Initial high throughput screening efforts identified highly potent and selective kappa opioid receptor antagonist 3 (kappa IC50 = 77 nM; mu:kappa and mu:kappa IC50 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 kappa antagonism as well as good brain exposure. Analog 6c (kappa IC50 = 20 nM; mu:kappa = 36, delta:kappa = 415) was also shown to reverse kappa-agonist induced rat diuresis in vivo. (C) 2010 Published by Elsevier Ltd.