Iturriaga-Vásquez Patricio, Miquel Raquel, Ivorra M Dolores, D'Ocon M Pilar, Cassels Bruce K
Millennium Institute for Advanced Research in Cell Biology and Biotechnology and Departamento de Química, Facultad de Ciencias, Universidad de Chile, Casilla 653, Santiago, Chile.
J Nat Prod. 2003 Jul;66(7):954-7. doi: 10.1021/np030022+.
A series of O- and/or N-substituted derivatives of (+/-)-coclaurine (1a) were synthesized as simplified structural mimics of the antihypertensive alkaloid tetrandrine (2) and assayed for binding to brain cortical sites labeled with the alpha(1)-adrenergic radioligand [(3)H]prazosin or the calcium channel radioligand [(3)H]diltiazem. The introduction of O-benzyl groups on the coclaurine molecule, which exhibits only adrenergic antagonist activity, led to the appearance of calcium channel blocking activity comparable to that of tetrandrine while retaining adrenolytic activity in the same concentration range. Contraction of aortal rings with noradrenaline or KCl was relaxed more potently by some of these coclaurine derivatives than by tetrandrine, suggesting leads for the development of novel antihypertensive drugs with a dual mechanism of action.
合成了一系列（±）-荷包牡丹碱（1a）的O-和/或N-取代衍生物，作为抗高血压生物碱粉防己碱（2）的简化结构模拟物，并测定其与用α（1）-肾上腺素能放射性配体[（3）H]哌唑嗪或钙通道放射性配体[（3）H]地尔硫卓标记的脑皮质位点的结合情况。在仅表现出肾上腺素能拮抗剂活性的荷包牡丹碱分子上引入O-苄基，导致出现了与粉防己碱相当的钙通道阻断活性，同时在相同浓度范围内保留了抗肾上腺素能活性。这些荷包牡丹碱衍生物中的一些比粉防己碱更有效地松弛了去甲肾上腺素或氯化钾引起的主动脉环收缩，这为开发具有双重作用机制的新型抗高血压药物提供了线索。
