Quaglia W, Pigini M, Tayebati S K, Piergentili A, Giannella M, Leonardi A, Taddei C, Melchiorre C
Department of Chemical Sciences, University of Camerino, Italy.
J Med Chem. 1996 May 24;39(11):2253-8. doi: 10.1021/jm960069a.
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)-alpha-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 alpha 1, alpha 2, 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 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 selective 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 enantiomer (-)-2 displayed selectivities of 12000-, 2500-, and 250-fold in binding to alpha 1a-adrenoreceptors relative to alpha 2-adrenoreceptors and 5-HT1A and D2 receptors. These results indicate that (-)-2 may be a valuable tool in the characterization of alpha 1-adrenoreceptor subtypes.
反式-[2-(2,6-二甲氧基苯氧基)乙基][(3-对甲苯基-2,3-二氢-1,4-苯并二恶英-2-基)甲基]胺（美芬二恶烷，2）的对映体由手性反式-3-对甲苯基-2,3-二氢-1,4-苯并二恶英-2-羧酸[(+)-3和(-)-3]合成，而这两种羧酸又是通过用(R)-和(S)-α-甲基苄胺拆分外消旋酸得到的。将2的对映体的圆二色光谱与(2S,3S)-3-甲基-2-苯基-1,4-苯并二恶烷的圆二色光谱进行比较，可将2的(-)-对映体指定为2S,3S构型，另一个对映体指定为2R,3R构型。与WB 4101（1）、5-甲基尿嘧啶和(+)-尼莫地平相比，评估了2的对映体在α1、α2、D2和5-HT1A受体上的结合情况。此外，还研究了这两种对映体在天然和克隆的α1-肾上腺素能受体亚型上的情况。在功能和结合试验中，(-)-2在α1-肾上腺素能受体亚型上的效力是(+)-对映体的10至30倍。它对α1A-肾上腺素能受体相对于α1B-肾上腺素能受体的选择性为36倍，在与α1a-肾上腺素能受体结合时相对于α1b和α1d亚型的选择性分别为60倍和20倍。此外，对映体(-)-2在与α1a-肾上腺素能受体结合时相对于α2-肾上腺素能受体以及5-HT1A和D2受体的选择性分别为12000倍、2500倍和250倍。这些结果表明，(-)-2可能是表征α1-肾上腺素能受体亚型的有价值工具。
