Only One Pharmacophore Is Required for the k Opioid Antagonist Selectivity of Norbinaltorphimine

We have investigated whether one or two pharmacophores are required for the k 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 k antagonist. Since 2 contains only one antagonist pharmacophore but yet retains substantial k selectivity, it is concluded that k selectivity is not dependent on the presence of two (-)-naltrexone-derived pharmacophores of 1. It is suggested that the selectivity k 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 k opioid receptors.