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 (κ IC₅₀ = 77 nM; μ:κ and δ:κ 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 κ antagonism as well as good brain exposure. Analog 6c (κ IC₅₀ = 20 nM; μ:κ = 36, δ:κ = 415) was also shown to reverse κ-agonist induced rat diuresis in vivo.