DeBernardis J F, Arendsen D L, Kyncl J J, Kerkman D J
J Med Chem. 1987 Jan;30(1):178-84. doi: 10.1021/jm00384a030.
The synthesis of a series of 1-(aminomethyl)phthalans 1b is reported. The radioligand binding to alpha 1- and alpha 2-receptors and the in vitro pharmacology in alpha 1 (rabbit aorta) and alpha 2 (phenoxybenzamine-pretreated dog saphenous vein) tissues were determined and were compared to the activity of the corresponding 1-(aminomethyl)indans. The activity of this series of phthalans was found to be consistent with the electrostatic repulsion hypothesis that was used to design the parent indan (ERBCOP) compounds. The effect of the phthalan ring oxygenation was to somewhat improve alpha 1-receptor potency relative to the 6-ERBCOP indans without having a general effect on the alpha 2-receptor potency. We conclude from the overall pattern of activity that while the norepinephrine type beta-hydroxyl group may be beneficial for binding to the alpha 1-adrenoceptor, it is not required for strong binding to or full stimulation of the alpha 2-adrenergic receptor, provided that the conformational mobility associated with the phenylethylamine is restricted and maintained in a favorable conformation for receptor interaction.
报道了一系列1-(氨甲基)酞嗪1b的合成。测定了放射性配体与α1和α2受体的结合以及在α1（兔主动脉）和α2（经酚苄明预处理的犬大隐静脉）组织中的体外药理学，并与相应的1-(氨甲基)茚满的活性进行了比较。发现该系列酞嗪的活性与用于设计母体茚满（ERBCOP）化合物的静电排斥假说一致。酞嗪环氧化的作用是相对于6-ERBCOP茚满在一定程度上提高α1受体效价，而对α2受体效价没有普遍影响。从总体活性模式我们得出结论，虽然去甲肾上腺素型β-羟基基团可能有利于与α1-肾上腺素能受体结合，但对于与α2-肾上腺素能受体的强烈结合或充分刺激并非必需，前提是与苯乙胺相关的构象流动性受到限制并保持有利于受体相互作用的构象。
