Stereochemical studies on medicinal agents. 31. Only one pharmacophore is required for the .kappa. opioid antagonist selectivity of norbinaltorphimine

1 July 1988

journal article
research article
Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry

Vol. 31 (7) , 1344-1347
https://doi.org/10.1021/jm00402a015

Abstract

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 [guinea pig] 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 seconds halves of these molecules in that they mimic key "address" components of dynorphin at .kappa. opioid receptors.

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