455311-42-9Relevant articles and documents
Highly potent and selective phenylmorphan-based inverse agonists of the opioid δ receptor
Thomas, James B.,Zhang, Li,Navarro, Hernán A.,Carroll, F. Ivy
, p. 5597 - 5609 (2007/10/03)
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 δ 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 δ 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]GTPγS functional assay with δ opioid receptor selectivity ratios of 103- and 132-fold versus the μ and κ opioid receptors, respectively. The compounds showed no agonist activity at any of the three opioid receptors; however, measurements of δ inverse agonist activity within this series illustrated a broad range of negative efficacy and IC50 values 650-fold more potent than the prototypical δ opioid receptor inverse agonist ICI 174 864 (22).