Synthesis of new opioid derivatives with a propellane skeleton and their pharmacology. Part 2 : Propellane derivatives with an amide side chain
Synthesis of new opioid derivatives with a propellane skeleton and their pharmacology. Part 2 : Propellane derivatives with an amide side chain
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具有丙烷骨架的新型阿片衍生物的合成及其药理学。
DOI：
10.1016/j.bmcl.2012.02.082
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发表时间：
2012
期刊：
影响因子：
--
通讯作者：
Hideaki Fujii
中科院分区：
文献类型：
--
作者：
Hiroshi Nagase;Junko Akiyama;Ryo Nakajima;Shigeto Hirayama;Toru Nemoto;Hiroaki Gouda;Shuichi Hirono;Hideaki Fujii
根据κ选择性激动剂纳呋拉芬的活性构象，设计合成了6-或7-酰胺侧链的螺桨烷衍生物。6-酰胺类化合物对κ受体有较高的亲和力，其中一种β-酰胺类化合物对κ受体的选择性高于纳呋拉芬。另一方面，尽管7-酰胺的亲和力比6-酰胺降低，但在测试的化合物中，一些7α-酰胺显示出对κ受体的最高选择性。7个β-异构体的亲和力极低，推测这是由于7β-酰胺侧链对17-氮上的孤电子对的屏蔽作用。这是螺桨烷衍生物中7-酰胺侧链的第一个构象信息。
We designed and synthesized propellane derivatives with a 6- or 7-amide side chain on the basis of the active conformation of the κ selective agonist nalfurafine. The 6-amides showed high affinities for the κ receptor, and one of the 6β-amides showed higher κ selectivity than nalfurafine. On the other hand, although the affinities of the 7-amides decreased compared to the 6-amides, some 7α-amides showed the highest selectivities for the κ receptor among the tested compounds. The affinities of 7β-isomers were extremely low, which was postulated to result from the shielding effect of the 7β-amide side chain against the lone electron pair on the 17-nitrogen. This is the first conformational information about the 7-amide side chain in propellane derivatives.