Only one pharmacophore is required for the kappa opioid antagonist selectivity of norbinaltorphimine.

We have investigated whether one or two pharmacophores are required for the kappa opioid receptor selectivity of the bivalent opioid antagonist norbinaltorphimine, (-)-1 (nor-BNI), by the synthesis and testing of its meso isomer 2. In smooth muscle preparations 2 was more potent than 1 and about half as selective as a kappa antagonist. Since 2 contains only one antagonist pharmacophore but yet retains substantial kappa selectivity, it is concluded that kappa selectivity is not dependent on the presence of two (-)-naltrexone-derived pharmacophores of 1. It is suggested that the kappa selectivity of (-)-1 and 2 is derived from the portions of the second halves of these molecules in that they mimic key "address" components of dynorphin at kappa opioid receptors.