Synthesis and biological evaluation of 14-alkoxymorphinans. 21. Novel 4-alkoxy and 14-phenylpropoxy derivatives of the mu opioid receptor antagonist cyprodime.
Synthesis and biological evaluation of 14-alkoxymorphinans. 21. Novel 4-alkoxy and 14-phenylpropoxy derivatives of the mu opioid receptor antagonist cyprodime.
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14-烷氧基吗啡喃的合成和生物学评价。
DOI：
10.1021/jm031126k
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发表时间：
2004
影响因子：
7.3
通讯作者：
Schmidhammer,Helmut
中科院分区：
文献类型：
--
作者：
Spetea,Mariana;Schüllner,Falko;Moisa,RaduC;Berzetei-Gurske,IlonaP;Schraml,Barbara;Dörfler,Cynthia;Aceto,MarioD;Harris,LouisS;Coop,Andrew;Schmidhammer,Helmut
介绍了新型环菌素衍生物的合成、生物学和药理评价。用受体结合实验评价它们与μ，δ和κ阿片受体的结合亲和力。我们观察到这些化合物的亲和力对4位取代基的性质和长度很敏感。环菌素(1)及其4-丁氧基类似物2的4-烷氧基的进一步延长不利于μ阿片受体的亲和力。在苯氧基的情况下，在C-4上引入芳基烷氧基不会增加μ亲和力，而苯丙氧基降低μ亲和力。与参考化合物相比，δ和κ的亲和力也降低了。通过引入14-苯丙氧基，显著提高了μ阿片受体的亲和力。δ和κ受体的亲和力也增加。这些发现进一步证明，14位取代基的性质对吗啡与阿片受体相互作用的能力有重大影响。在[35S]GTPγS结合实验中，所有受试化合物都是μ和δ受体的部分激动剂。化合物8和17对κ受体有拮抗作用，而化合物7对该受体有部分激动剂活性。含有14-苯丙氧基的新型环菌胺衍生物是一种有效的抗伤害药物。在体内试验中，化合物7、8和17比吗啡有效得多，其中酚7在小鼠体内表现出最高的抗伤害性效力(在热板试验中是21倍，在甩尾试验中是38倍，在对苯二酚扭体试验中是300倍)。14-苯丙氧基取代基的引入使这类化合物的药理性质发生了深刻的变化。
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 analogue2is 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 [35S]GTPγS binding assay, all tested compounds were partial agonists at μ and δ receptors. Compounds8and17showed antagonism at κ receptors, while compound7exhibited 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, compounds7,8, and17were considerably more potent than morphine, with phenol7showing 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.