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

A structurally novel opioid delta 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 [(35)S]GTPgammaS functional assay. (+)-KF4 is also a delta inverse agonist with an IC(50) value of 1.8 nM. To our knowledge, this is the first potent and selective delta opioid receptor antagonist from the 5-phenylmorphan class of opioids.