Synthesis, Absolute Configuration, and Biological Profile of the Enantiomers oftrans-[2-(2,6-Dimethoxyphenoxy)ethyl][(3-p-tolyl-2,3-dihydro-1,4- benzodioxin-2-yl)methyl]amine (Mephendioxan), a Potent Competitive α1A-Adrenoreceptor Antagonist

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Abstract
The enantiomers of trans-[2-(2,6-dimethoxyphenoxy)ethyl][(3-p-tolyl-2,3-dihydro-1,4-benzodioxin-2-yl)methyl]amine (mephendioxan, 2) were synthesized from the chiral trans-3-p-tolyl-2,3-dihydro-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)-α-methylbenzylamine. Comparison of CD spectra of the enantiomers of 2 with that of (2S,3S)-3-methyl-2-phenyl-1,4-benzodioxane allowed 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 α1, α2, D2, and 5-HT1A receptors, in comparison to WB 4101 (1), 5-methylurapidil, and (+)-niguldipine. In addition, the two enantiomers were investigated at native and cloned α1-adrenoreceptor subtypes. (−)-2 was 10−30 times as potent as the (+)-enantiomer at α1-adrenoreceptor subtypes in both functional and binding assays. It was 36-fold selective for the α1A- versus α1B-adrenoreceptor and 60- and 20-fold selective in binding to the α1a-adrenoreceptor relative to α1b and α1d subtypes, respectively. Furthermore, the enantiomer (−)-2 displayed selectivities of 12000-, 2500-, and 250-fold in binding to α1a-adrenoreceptors relative to α2-adrenoreceptors and 5-HT1A and D2 receptors. These results indicate that (−)-2 may be a valuable tool in the characterization of α1-adrenoreceptor subtypes.

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