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首页> 外文期刊>Journal of Medicinal Chemistry >Synthesis and Biological Evaluation of 14-Alkoxymorphinans. 21. Novel 4-Alkoxy and 14-Phenylpropoxy Derivatives of the μ Opioid Receptor Antagonist Cyprodime
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Synthesis and Biological Evaluation of 14-Alkoxymorphinans. 21. Novel 4-Alkoxy and 14-Phenylpropoxy Derivatives of the μ Opioid Receptor Antagonist Cyprodime

机译：14-烷氧基吗啡喃的合成及生物学评价。 21.μ阿片受体拮抗剂Cyprodime的新型4-烷氧基和14-苯丙氧基衍生物

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The synthesis, biological, and pharmacological evaluation of novel derivatives of cyprodime are described. Their binding affinities at μ, δ, and κ opioid receptors were evaluated using receptor binding assay. It was observed that the affinity of these compounds was sensitive to the character and length of the substituent in position 4. Further prolongation of the 4-alkoxy group of cyprodime (1) and its 4-butoxy analogue 2 is detrimental for the μ opioid receptor affinity. Introduction of an arylalkoxy group at C-4 does not increase μ affinity in the case of benzyloxy, while a phenylpropoxy group reduces μ affinity. The δ and κ affinities were also reduced compared to the reference compounds. A significant increase in the affinity at the μ opioid receptors was achieved by introducing a 14-phenylpropoxy group. Increases in the affinity at δ and κ receptors were also observed. These findings provide further evidence that the nature of the substituent at position 14 has a major impact on the abilities of morphinans to interact with opioid receptors. In the [~(35)S]GTPS binding assay, all tested compounds were partial agonists at μ and δ receptors. Compounds 8 and 17 showed antagonism at κ receptors, while compound 7 exhibited some partial agonist activity at this receptor. The novel derivatives of cyprodime containing a 14-phenylpropoxy group acted as potent antinociceptives. When tested in vivo, compounds 7, 8, and 17 were considerably more potent than morphine, with phenol 7 showing the highest antinociceptive potency (21-fold in the hot plate test, 38-fold in the tail flick test, and 300-fold in the paraphenylquinone writhing test) in mice. Introduction of a 14-phenylpropoxy substituent leads to a profound alteration in the pharmacological profile of this class of compounds.
机译：描述了新的嘧啶衍生物的合成，生物学和药理学评价。使用受体结合测定法评估它们在μ，δ和κ阿片受体上的结合亲和力。观察到这些化合物的亲和力对位置4上的取代基的特性和长度敏感。环丙啶（1）的4​​-烷氧基和其4-丁氧基类似物2的进一步延长对μ阿片样物质受体有害。亲和力。在苄氧基的情况下，在C-4处引入芳基烷氧基不会增加μ亲和力，而苯基丙氧基会降低μ亲和力。与参考化合物相比，δ和κ亲和力也降低了。通过引入14-苯基丙氧基，可显着提高对μ阿片受体的亲和力。还观察到了对δ和κ受体的亲和力增加。这些发现提供了进一步的证据，表明第14位取代基的性质对吗啡喃与阿片样物质受体相互作用的能力有重大影响。在[〜（35）S] GTPS结合试验中，所有测试的化合物均为μ和δ受体的部分激动剂。化合物8和17在κ受体上显示出拮抗作用，而化合物7在该受体上显示出部分激动剂活性。含有14-苯基丙氧基的新嘧啶衍生物可作为有效的镇痛药。当在体内进行测试时，化合物7、8和17比吗啡有效得多，苯酚7的抗伤害力最高（热板测试为21倍，甩尾测试为38倍，而甩尾测试为300倍）在对苯醌扭曲试验中）。 14-苯基丙氧基取代基的引入导致这类化合物的药理学性质发生深刻变化。

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