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 (Ke = 0.1 nM) in the [35S]GTPgammaS 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).