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Identification and synthesis of norhydromorphone, and determination of antinociceptive activities in the rat formalin test

机译：去甲福尔马林试验中去氢吗啡酮的鉴定，合成及抗伤害感受活性的测定

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The main objective of this paper is to report the identification and synthesis of norhydromorphone, a novel metabolite of hydromorphone, and its antinociceptive activities when tested in the formalin test as compared to other known analgesics. In addition, we are reporting for the first time the lack of antinociceptive activities of hydromorphone-3-glucuronide, dihydromorphine-3-glucuronide and dihydroisomorphine-3-glucuronide in the rat formalin test. Norhydromorphone was isolated and identified as a metabolite of hydromorphone in a cancer patient's urine. An authentic standard of norhydromorphone was synthesized. The identity of norhydromorphone in the urine sample was confirmed by comparing the LC retention time and MS ion fragmentation with the synthetic standard using a liquid chromatographic-mass spectrometric-mass spectrometric (LC-MS-MS) assay. Norhydromorphone was found to be a minor metabolite of hydromorphone in the urine. Additionally, the antinociceptive activities of norhydromorphone, hydromorphone, morphine, dihydromorphine, dihydroisomorphine, hydromorphone-3-glucuronide, dihydromorphine-3-glucuronide and dihydroisomorphine-3-glucuronide were determined in the rat formalin test following intraperitoneal (i.p.) administration. Only limited antinociception was observed and no significant increase in antinociception was detected at the three doses tested. The increased polarity of norhydromorphone as compared to hydromorphone due to the primary piperidine nitrogen may make it less favorable to cross the blood-brain-barrier (BBB), which may be partly responsible. In addition, lower intrinsic antinociceptive activity, which remains to be determined, could also contribute to the low antinociception. Our results also show that hydromorphone was five times as potent as morphine in the formalin test, while dihydromorphine and dihydroisomorphine were equipotent to and 36% as potent as morphine, respectively. Hydromorphone-3-glucuronide, dihydromorphine-3-glucuronide and dihydroisomorphine-3-glucuronide did not exhibit any antinociceptive effect at the doses tested. The results further underscore the importance of a free C-3-OH to the analgesic effect of morphine alkaloids. (C) 2004 Elsevier Inc. All rights reserved.
机译：本文的主要目的是报告福尔马林试验中与其他已知的镇痛药相比，吗啡新代谢物去氢吗啡酮的鉴定和合成及其抗伤害感受活性。此外，我们首次报道了在大鼠福尔马林试验中氢吗啡酮-3-葡糖醛酸，二氢吗啡-3-葡糖醛酸和二氢异吗啡-3-葡糖醛酸的抗伤害感受活性。分离出去氢吗啡酮并鉴定为癌症患者尿液中的氢吗啡酮代谢物。合成了标准的去氢吗啡酮。通过使用液相色谱-质谱-质谱法（LC-MS-MS）将LC保留时间和MS离子碎片与合成标准品进行比较，确认了尿样中去氢吗啡酮的身份。发现去氢吗啡酮是尿液中氢吗啡酮的次要代谢产物。另外，在腹膜内（i.p.）给药后，在大鼠福尔马林试验中测定了去氢吗啡酮，氢吗啡酮，吗啡，二氢吗啡，二氢异吗啡，氢吗啡酮-3-葡糖醛酸，二氢吗啡-3-葡糖醛酸和二氢异吗啡-3-葡糖醛酸的抗伤害感受活性。在三个测试剂量下，仅观察到有限的抗伤害感受，并且未检测到抗伤害感受的显着增加。由于氢哌啶氮的作用，与氢吗啡酮相比，去氢吗啡酮的极性增加，可能不利于穿越血脑屏障（BBB），这可能是部分原因。此外，尚待确定的较低的固有抗伤害感受活性也可能导致较低的抗伤害感受。我们的结果还表明，在福尔马林试验中，氢吗啡酮的效力是吗啡的五倍，而二氢吗啡和二氢异吗啡的效力分别是吗啡的36％。在所测试的剂量下，氢吗啡酮-3-葡糖醛酸，二氢吗啡-3-葡糖醛酸和二氢异吗啡-3-葡糖醛酸没有显示任何抗伤害感受的作用。结果进一步强调了游离的C-3-OH对吗啡生物碱镇痛作用的重要性。 （C）2004 Elsevier Inc.保留所有权利。

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