SYNTHESIS, ASSIGNMENT OF ABSOLUTE-CONFIGURATION, AND RECEPTOR-BINDING STUDIES RELEVANT TO THE NEUROLEPTIC ACTIVITIES OF A SERIES OF CHIRAL 3-SUBSTITUTED CYPROHEPTADINE ATROPISOMERS

The syntheses and resolutions of chiral analogues of cyproheptadine bearing a cyano (1) and a trifluoromethylsulfonyl (8) suhstituent in the 3 position are described. The absolute configuration of (-)-3-bromocyproheptadine (5) was determined by X-ray crystal structure analysis to be pRapSb. The absolute configurations of 1, 8, and five other pairs of 3-substituted cyproheptadine analogues were related to the 3-bromo compound by circular dichroism spectrophotometry. The binding affinities of each member of the eight pairs of atropisomers as well as the parent unsubstituted cyproheptadine to membrane sites specifically binding tritiated ligands comprising the a-adrenergic agonist (-)-[3H] norepinephrine, the a-adrenergic antagonist [[[2-(2ʹ,6ʹ-[3H]dimethoxyphenoxy)ethyl]amino]-methyl]benzodioxane (WB-4101), the dopamine antagonist [3H]spiroperidol, and the muscarinic cholinergic antagonist [3H]quinuclidinyl benzilate (QNB) were measured by displacing these ligands from membrane preparations of mammalian brain. [34H]QNB was uniformly more easily displaced by the pSaRb absolute configuration of each pair, while the remaining three ligands were more easily displaced by isomers of the pSaRb configuration. Quantitative structure-activity relationships demonstrate only modest correlations between the receptor binding data and physical parameters of the 3-substituents, indicating the complex nature of the drug-receptor interactions. © 1979, American Chemical Society. All rights reserved.