Ivorra M D, Chuliá S, Lugnier C, D'Ocon M P
Departamento de Farmacologia, Facultad de Farmacia, Universitat de Valencia, Spain.
Eur J Pharmacol. 1993 Feb 9;231(2):165-74. doi: 10.1016/0014-2999(93)90445-n.
Contractions evoked by noradrenaline (1 microM) or a depolarizing solution of 60 mM KCl were concentration dependently depressed by the aporphine alkaloids (S)-boldine and (R)-apomorphine in rat aorta. Both drugs had a greater inhibitory potency on the contraction elicited by noradrenaline. Dose-response curves for noradrenaline were shifted to the right in presence of (S)-boldine. (R)-Apomorphine acted by a complex mechanism at alpha 1-adrenoceptors and its inhibitory effect was irreversible. The conformational features of these alkaloids may explain their different behaviour at alpha 1-adrenoceptors. In Ca(2+)-free solution, the alkaloids inhibited the contraction evoked by noradrenaline but did not modify (apomorphine) or increase (boldine) the contractile response induced by caffeine. Both alkaloids interacted with [3H]prazosin binding and with the benzothiazepine binding site of the Ca2+ entry receptor complex but had no effect at the dihydropyridine binding site in the rat cerebral cortex. Both drugs showed some selectivity as inhibitors of [3H]prazosin binding as opposed to [3H]d-cis diltiazem binding. (R)-Apomorphine slightly inhibited one of the two forms of the Ca(2+)-independent, low Km cyclic AMP-phosphodiesterase (type IV), whereas it did not have a significant effect on the other phosphodiesterase forms. (S)-Boldine had negligible inhibitory effects on all phosphodiesterase forms. The present study provides evidence that (S)-boldine and (R)-apomorphine have interesting properties as Ca2+ entry blockers (through the benzothiazepine receptor site in the Ca2+ channel) and at alpha 1-adrenoceptors.
在大鼠主动脉中，去甲肾上腺素（1微摩尔）或60毫摩尔氯化钾的去极化溶液诱发的收缩，被阿朴啡生物碱（S）-去甲乌药碱和（R）-阿扑吗啡浓度依赖性地抑制。两种药物对去甲肾上腺素诱发的收缩具有更强的抑制效力。在（S）-去甲乌药碱存在的情况下，去甲肾上腺素的剂量-反应曲线向右移动。（R）-阿扑吗啡通过复杂机制作用于α1-肾上腺素受体，其抑制作用是不可逆的。这些生物碱的构象特征可能解释了它们在α1-肾上腺素受体上的不同行为。在无钙溶液中，生物碱抑制去甲肾上腺素诱发的收缩，但不改变（阿扑吗啡）或增加（去甲乌药碱）咖啡因诱导的收缩反应。两种生物碱都与[3H]哌唑嗪结合以及Ca2+进入受体复合物的苯并硫氮䓬结合位点相互作用，但对大鼠大脑皮层中的二氢吡啶结合位点没有影响。与[3H]-d-顺式地尔硫䓬结合相比，两种药物作为[3H]哌唑嗪结合的抑制剂都表现出一定的选择性。（R）-阿扑吗啡轻微抑制两种形式的非钙依赖性、低Km环磷酸腺苷磷酸二酯酶（IV型）中的一种，而对其他磷酸二酯酶形式没有显著影响。（S）-去甲乌药碱对所有磷酸二酯酶形式的抑制作用可忽略不计。本研究提供了证据，表明（S）-去甲乌药碱和（R）-阿扑吗啡作为Ca2+进入阻滞剂（通过Ca2+通道中的苯并硫氮䓬受体位点）以及在α1-肾上腺素受体方面具有有趣的特性。
