Discovery of the first N-substituted 4β-methyl-5-(3-hydroxyphenyl) morphan to possess highly potent and selective opioid δ receptor antagonist activity

A structurally novel opioid 6 receptor selective antagonist has been identified. This compound, (+)-5-(3-hydroxyphenyl)-4-methyl-2-(3-phenylpropyl)-2-azabicyclo[3.3.1]-non-7-yl-(1- phenyl-1-cyclopentane)carboxamide [(+)-KF4, (+)4], showed a K-e value of 0.15 nM in the [S-35]GTPgammaS functional assay. (+)-KF4 is also a 6 inverse agonist with an IC50 value of 1.8 nM. To our knowledge, this is the first potent and selective 6 opioid receptor antagonist from the 5-phenylmorphan class of opioids.