Highly potent and selective phenylmorphan-based inverse Agonists of the opioid δ receptor

We recently reported the discovery of (+)-5-( 3-hydroxyphenyl)-4-methyl-2-( 3-phenylpropyl)-2-azabicyclo-[ 3.3.1] non-7-yl-( 1-phenyl-1-cyclopentane) carboxamide [(+)-KF4, (+)-5] as a novel chemotype possessing potent antagonist activity at the delta opioid receptor. Additional SAR studies involving changes to both the 2-amino and 7-amido N-substituents using this same (+)- morphan scaffold have revealed compounds with improved potency and selectivity for the delta opioid receptor. The highly potent and selective 2,2-dimethylphenylacetamide analogue (+)- N-[( 1S, 4R, 5R, 7S)-5-( 3-hydroxyphenyl)-4-methyl- 2-(3-phenylpropyl)2- azabicyclo[ 3.3.1] non-7-yl]-2-methyl-2-phenylpropanamide ( 13d, delmorphan-A) showed picomolar inhibitory potency ( K-e = 0.1 nM) in the [ S-35] GTP gamma S functional assay with delta opioid receptor selectivity ratios of 103- and 132- fold versus the mu and kappa opioid receptors, respectively. The compounds showed no agonist activity at any of the three opioid receptors; however, measurements of delta inverse agonist activity within this series illustrated a broad range of negative efficacy and IC50 values 650-fold more potent than the prototypical delta opioid receptor inverse agonist ICI 174 864 ( 22).