Sandulenko Irina V, Belozertseva Irina V, Zvartau Edwin E, Zelentsova Maria V, Ambartsumyan Asmik A, Smol'yakov Alexander F, Moiseev Sergey K
A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, ul. Vavilova 28, bld. 1, Moscow, 119334, Russia.
Pavlov First Saint Petersburg State Medical University, L'va Tolstogo str. 6-8, St. Petersburg, 197022, Russia.
Eur J Med Chem. 2023 Apr 5;252:115296. doi: 10.1016/j.ejmech.2023.115296. Epub 2023 Mar 22.
Thevinols and their 3-O-demethylated relatives, orvinols, are derivatives of the Diels-Alder adduct of natural alkaloid thebaine with methyl vinyl ketone. Taken together, thevinols and orvinols constitute an important family of opioid receptor (OR) ligands playing an important role in both the OR mediated antinociception and OR antagonism. Herein, we disclose for the first time the OR activity of orvinols fluorinated within the pharmocophore associated with C(20) and its surrounding along with a dependence of the activity profile on the substituent at N(17). Starting from thevinone and 18,19-dihydrothevinone, a family of C(21)-fluorinated orvinols bearing methyl, cyclopropylmethyl (CPM), and allyl substituent at N(17) was synthesized. The fluorinated compounds were evaluated for OR activity. The orvinols bearing three fluorine atoms at C(21) were found to retain the properties of OR ligands and their activity profile depends on the substituent at N(17). Pilot in vivo experiments in a model of acute pain (tail-flick test in mice) revealed that 6-O-desmethyl-21,21,21-trifluoro-20-methylorvinol at doses 1.0-10.0 mg/kg (s.c.) exhibits analgesic activity at the level of morphine for a duration of 30-180 min. Its N(17)-CPM counterpart demonstrated the partial opioid agonist properties. The N(17)-allyl substituted derivative showed no analgesic activity. In vivo evaluation of an analgesic activity indicates that 21,21,21-trifluoro-20-methylorvinols represent a novel family of OR ligands related to buprenorphine, diprenorphine, etc. These compounds are promising for the structure-activity relationship studies among the thevinol/orvinol series as well as for a search for new OR ligands with potentially valuable pharmacological profiles.
蒂夫诺醇及其3 - O - 去甲基衍生物奥夫诺醇，是天然生物碱蒂巴因与甲基乙烯基酮的狄尔斯 - 阿尔德加合物的衍生物。蒂夫诺醇和奥夫诺醇共同构成了一类重要的阿片受体（OR）配体，在OR介导的抗伤害感受和OR拮抗作用中都发挥着重要作用。在此，我们首次披露了在与C(20)及其周围相关的药效团内进行氟化的奥夫诺醇的OR活性，以及活性谱对N(17)处取代基的依赖性。从蒂夫诺酮和18,19 - 二氢蒂夫诺酮出发，合成了一系列在N(17)处带有甲基、环丙基甲基（CPM）和烯丙基取代基的C(21) - 氟化奥夫诺醇。对这些氟化化合物进行了OR活性评估。发现在C(21)处带有三个氟原子的奥夫诺醇保留了OR配体的性质，并且它们的活性谱取决于N(17)处的取代基。在急性疼痛模型（小鼠甩尾试验）中的初步体内实验表明，6 - O - 去甲基 - 21,21,21 - 三氟 - 20 - 甲基奥夫诺醇在剂量为1.0 - 10.0 mg/kg（皮下注射）时，表现出与吗啡相当的镇痛活性，持续时间为30 - 180分钟。其N(17) - CPM对应物表现出部分阿片类激动剂性质。N(17) - 烯丙基取代衍生物未表现出镇痛活性。镇痛活性的体内评估表明，21,21,21 - 三氟 - 20 - 甲基奥夫诺醇代表了一类与丁丙诺啡、二丙诺啡等相关的新型OR配体。这些化合物对于蒂夫诺醇/奥夫诺醇系列的构效关系研究以及寻找具有潜在有价值药理特性的新OR配体很有前景。
