SYNTHESIS, ABSOLUTE-CONFIGURATION, AND BIOLOGICAL PROFILE OF THE ENANTIOMERS OF OLYL-2,3-DIHYDRO-1,4-BENZODIOXIN-2-YL)METHYL]AMINE (MEPHENDIOXAN), A POTENT COMPETITIVE ALPHA(1A)-ADRENOCEPTOR ANTAGONIST

The enantiomers of olyl-2,3-dihydro-1,4-benzodioxin-2-yl)methyl]amine (mephendioxan, 2) were synthesized from the chiral 3-p-tolyl-2,3-dihyd ro-1,4-benzodioxin-2-carboxylic acids [(+)-3 and (-)-3] which in turn were obtained through the resolution of the racemic acid with (R)- and (S)-alpha-methylbenzylamine. Comparison of CD spectra of the enantiom ers of 2 with that of (2S,3S)-3-methyl-2-phenyl-1,4-benzodioxane allow ed the assignment of the 2S,3S configuration to the (-)-enantiomer of 2 and of the 2R,3R configuration to the other enantiomer. The binding profile of the enantiomers of 2 was assessed at alpha(1), alpha(2), D- 2, and 5-HT1A receptors, in comparison to WB 4101 (1), 5-methylurapidi l, and (+)-niguldipine. In addition, the two enantiomers were investig ated at native and cloned alpha(1)-adrenoreceptor subtypes. (-)-2 was 10-30 times as potent as the (+)-enantiomer at alpha(1)-adrenoreceptor subtypes in both functional and binding assays. It was 36-fold select ive for the alpha(1A)- versus alpha(1B)-adrenoreceptor and 60- and 20- fold selective in binding to the alpha(1a)-adrenoreceptor relative to alpha(1b) and alpha(1d) subtypes, respectively. Furthermore, the enant iomer (-)-2 displayed selectivities of 12000-, 2500-, and 250-fold in binding to alpha(1a)-adrenoreceptors relative to alpha(2)-adrenorecept ors and 5-HT1A and D-2 receptors. These results indicate that (-)-2 ma y be a valuable tool in the characterization of alpha(1)-adrenorecepto r subtypes.