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Initial high throughput screening efforts identified highly potent and selective kappa opioid receptor antagonist 3 (κ IC 50 =77nM; 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...
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