Engstrøm T, Barth T, Melin P, Vilhardt H
Department of Medical Physiology, The Panum Institute, University of Copenhagen, Denmark.
Eur J Pharmacol. 1998 Aug 21;355(2-3):203-10. doi: 10.1016/s0014-2999(98)00513-5.
Metabolites of the analogue 1-deamino-1-carba-2-tyrosine(O-methyl)-oxytocin (carbetocin) following incubation with a rat kidney homogenate were isolated and their pharmacodynamic properties investigated. Apart from the parent compound two metabolites were identified namely desGlyNH2-carbetocin (carbetocin metabolite I) and desLeuGlyNH2-carbetocin (carbetocin metabolite II). Both carbetocin, carbetocin metabolite I and carbetocin metabolite II displayed binding affinities to the myometrial oxytocin receptor of a similar magnitude as oxytocin. Carbetocin was found to have agonistic properties on isolated myometrial strips and it was found to exert this effect through generation of inositol phosphates, as is the case for oxytocin. However, maximal contractile effect of carbetocin was approximately 50% lower than that of oxytocin (2.70 +/- 0.12 g compared to 5.22 +/- 0.26 g) and EC50 was approximately ten times higher (48.0 +/- 8.20 nM compared to 5.62 +/- 1.22 nM). Neither carbetocin metabolite I nor carbetocin metabolite II were able to contract isolated myometrial tissue. All three compounds displayed antagonistic properties against oxytocin in vitro, with carbetocin being the strongest inhibitor (pA2 = 8.21) and carbetocin metabolite II (pA2 = 8.01) being stronger than carbetocin metabolite I (pA2 = 7.81). These results indicate that carbetocin is a partial agonist/antagonist to the oxytocin receptor while the two metabolites carbetocin metabolite I and carbetocin metabolite II are pure antagonists. All three analogues bound to the myometrial vasopressin V1 receptor, albeit with much lower affinities than to the oxytocin receptor. Carbetocin metabolite II showed the weakest binding affinity of 33.7 +/- 7.34 nM compared to 7.24 +/- 0.29 nM for carbetocin and 9.89 + 2.80 nM for carbetocin metabolite I. Only carbetocin bound to the renal vasopressin V2 receptor though the binding affinity was very low (61.3 +/- 14.6 nM).
将类似物1-脱氨基-1-碳-2-酪氨酸（O-甲基）-催产素（卡贝缩宫素）与大鼠肾脏匀浆孵育后，分离出其代谢产物，并对其药效学特性进行了研究。除母体化合物外，还鉴定出两种代谢产物，即去甘氨酰胺基卡贝缩宫素（卡贝缩宫素代谢产物I）和去亮氨酰甘氨酰胺基卡贝缩宫素（卡贝缩宫素代谢产物II）。卡贝缩宫素、卡贝缩宫素代谢产物I和卡贝缩宫素代谢产物II对子宫肌层催产素受体的结合亲和力与催产素相似。发现卡贝缩宫素对离体子宫肌条具有激动特性，并且发现它通过产生肌醇磷酸来发挥这种作用，催产素也是如此。然而，卡贝缩宫素的最大收缩效应比催产素低约50%（分别为2.70±0.12 g和5.22±0.26 g），半数有效浓度（EC50）约高十倍（分别为48.0±8.20 nM和5.62±1.22 nM）。卡贝缩宫素代谢产物I和卡贝缩宫素代谢产物II均不能使离体子宫肌组织收缩。这三种化合物在体外均表现出对催产素的拮抗特性，其中卡贝缩宫素是最强的抑制剂（pA2 = 8.21），卡贝缩宫素代谢产物II（pA2 = 8.01）比卡贝缩宫素代谢产物I（pA2 = 7.81）更强。这些结果表明，卡贝缩宫素是催产素受体的部分激动剂/拮抗剂，而两种代谢产物卡贝缩宫素代谢产物I和卡贝缩宫素代谢产物II是纯拮抗剂。这三种类似物均与子宫肌层血管加压素V1受体结合，尽管其亲和力远低于与催产素受体的结合亲和力。卡贝缩宫素代谢产物II的结合亲和力最弱，为33.7±7.34 nM相比，卡贝缩宫素为7.24±0.29 nM，卡贝缩宫素代谢产物I为9.89±2.80 nM。只有卡贝缩宫素与肾脏血管加压素V2受体结合，但其结合亲和力非常低（61.3±14.6 nM）。
