Yamamoto L T, Horie S, Takayama H, Aimi N, Sakai S, Yano S, Shan J, Pang P K, Ponglux D, Watanabe K
Laboratory of Chemical Pharmacology, Faculty of Pharmaceutical Sciences, Chiba University, Japan.
Gen Pharmacol. 1999 Jul;33(1):73-81. doi: 10.1016/s0306-3623(98)00265-1.
We have previously elucidated the opiate-like action of mitragynine, an active principle isolated from the Thai medicinal plant Mitragyna speciosa. In the present study, effects of the related compound, mitragynine pseudoindoxyl on electrically stimulated contraction in guinea pig ileum and mouse vas deferens, and on its binding affinity in the guinea pig brain membranes were studied. Mitragynine pseudoindoxyl inhibited the electrically stimulated ileum and mouse vas deferens contractions in a concentration-dependent manner. In the ileum, the effective concentration is in an nM order, being nearly equivalent to reported concentrations of the micro-opioid receptor agonist [D-Ala2, Met-Phe4, Gly-ol5] enkephalin (DAMGO), and is 100- and 20-fold smaller than those of mitragynine and morphine, respectively. In the vas deferens, it is 35-fold smaller than that of morphine. The inhibitory action of mitragynine pseudoindoxyl in the ileum was antagonized by the non-selective opioid receptor antagonist naloxone and the micro-receptor antagonist naloxonazine. It was also antagonized by the delta-receptor antagonist naltrindole in the vas deferens. Mitragynine pseudoindoxyl showed a similar binding affinity to DAMGO and naltrindole at micro- and delta-receptors, respectively. However, the affinity at kappa-receptors was negligible. The present study demonstrates that mitragynine pseudoindoxyl, a novel alkaloid structurally different from other opioid agonists, acts on opioid receptors, leading to a potent inhibition of electrically stimulated contraction in the ileum through the micro-receptors and in mouse vas deferens through delta-receptors.
我们之前已经阐明了从泰国药用植物美丽帽柱木中分离出的活性成分——帽柱木碱的阿片样作用。在本研究中，我们研究了相关化合物——帽柱木碱假吲哚对豚鼠回肠和小鼠输精管电刺激收缩的影响，以及对豚鼠脑膜中其结合亲和力的影响。帽柱木碱假吲哚以浓度依赖性方式抑制电刺激的回肠和小鼠输精管收缩。在回肠中，有效浓度处于纳摩尔级别，几乎等同于已报道的微阿片受体激动剂[D-丙氨酸2，甲硫氨酸-苯丙氨酸4，甘氨酸-醇5]脑啡肽（DAMGO）的浓度，分别比帽柱木碱和吗啡的有效浓度小100倍和20倍。在输精管中，它比吗啡的有效浓度小35倍。帽柱木碱假吲哚在回肠中的抑制作用可被非选择性阿片受体拮抗剂纳洛酮和微受体拮抗剂纳洛嗪拮抗。在输精管中，它也可被δ受体拮抗剂纳曲吲哚拮抗。帽柱木碱假吲哚在微受体和δ受体上分别显示出与DAMGO和纳曲吲哚相似的结合亲和力。然而，其在κ受体上的亲和力可忽略不计。本研究表明，帽柱木碱假吲哚是一种结构上不同于其他阿片激动剂的新型生物碱，作用于阿片受体，通过微受体导致对电刺激回肠收缩的强效抑制，并通过δ受体导致对小鼠输精管电刺激收缩的强效抑制。
