Reitz A B, Sonveaux E, Rosenkranz R P, Verlander M S, Melmon K L, Hoffman B B, Akita Y, Castagnoli N, Goodman M
J Med Chem. 1985 May;28(5):634-42. doi: 10.1021/jm50001a017.
A novel series of N-aminoalkyl congeners and model derivatives of norepinephrine has been synthesized. Compounds that were structurally related to epinephrine were prepared from fully protected intermediates. Alternatively, isoproterenol-related compounds were synthesized via reductive amination of preformed methyl ketone derivatives with norepinephrine. The beta-adrenergic activities of these new compounds were assessed through measurement of intracellular cyclic AMP accumulation in S49 mouse lymphoma cells and displacement of iodocyanopindolol (ICYP) from membrane preparations. Congeners that contained an underivatized primary amine function exhibited virtually no activity in these assays. However, when this amine function was acylated (e.g., to an amide, carbamate, urea, sulfonamide, etc.), the products exhibited generally increased beta-adrenergic activity, which was, however, strongly dependent on the nature of the acylating group and also the length of the spacer. In particular, a benzyl carbamate derivative containing a branched, seven-carbon spacer group was 40 times more potent than isoproterenol in the in vitro S49 assay.
已合成了一系列新型的去甲肾上腺素N-氨基烷基同系物和模型衍生物。与肾上腺素结构相关的化合物由完全保护的中间体制备。另外，与异丙肾上腺素相关的化合物通过预先形成的甲基酮衍生物与去甲肾上腺素的还原胺化反应合成。通过测量S49小鼠淋巴瘤细胞中细胞内环磷酸腺苷（cAMP）的积累以及从膜制剂中置换碘氰吲哚洛尔（ICYP）来评估这些新化合物的β-肾上腺素能活性。在这些测定中，含有未衍生化伯胺官能团的同系物几乎没有活性。然而，当该胺官能团被酰化（例如，形成酰胺、氨基甲酸酯、脲、磺酰胺等）时，产物通常表现出增强的β-肾上腺素能活性，然而，这强烈依赖于酰化基团的性质以及间隔基的长度。特别是，在体外S49测定中，含有支链七碳间隔基团的苄基氨基甲酸酯衍生物的效力比异丙肾上腺素高40倍。
