Synthesis and pharmacology of 1-alkyl-3-(1-naphthoyl)indoles: steric and electronic effects of 4- and 8-halogenated naphthoyl substituents.
Synthesis and pharmacology of 1-alkyl-3-(1-naphthoyl)indoles: steric and electronic effects of 4- and 8-halogenated naphthoyl substituents.
复制标题
1-烷基-3-(1-萘甲酰基)吲哚的合成和药理学：4-和8-卤代萘甲酰基取代基的空间和电子效应。
DOI：
10.1016/j.bmc.2012.01.038
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发表时间：
2012
影响因子：
3.5
通讯作者：
Huffman,JohnW
中科院分区：
文献类型：
--
作者：
Wiley,JennyL;Smith,ValerieJ;Chen,Jianhong;Martin,BillyR;Huffman,JohnW
为了开发在大麻素CB 1和CB 2受体上具有适度吸电子取代基的3-（1-萘甲酰基）吲哚的SAR，制备了1-丙基和1-戊基-3-（4-氟、氯、溴和碘-1-萘甲酰基）衍生物。为了研究萘甲酰基8位取代基的空间效应和电子效应，还合成了3-（4-氯、溴和碘-1-萘甲酰基）吲哚。测定了两组化合物对CB 1和CB 2受体的亲和力，并在小鼠体内评价了其中几种化合物。这些取代基对受体亲和力和体内活性的影响进行了讨论，并提出了结构-活性关系。尽管这些化合物中的许多对CB 2受体具有选择性，但只有三种JWH-423，1-丙基-3-（4-碘-1-萘甲酰基）吲哚，JWH-422，2-甲基-1-丙基-3-（4-碘-1-萘甲酰基）吲哚，JWH-423的2-甲基类似物和JWH-417，1-戊基-3-（8-碘-1-萘甲酰基）吲哚，具有低CB 1亲和力和良好CB 2亲和力的理想组合。
To develop SAR at both the cannabinoid CB1and CB2receptors for 3-(1-naphthoyl)indoles bearing moderately electron withdrawing substituents at C-4 of the naphthoyl moiety, 1-propyl and 1-pentyl-3-(4-fluoro, chloro, bromo and iodo-1-naphthoyl) derivatives were prepared. To study the steric and electronic effects of substituents at the 8-position of the naphthoyl group, the 3-(4-chloro, bromo and iodo-1-naphthoyl)indoles were also synthesized. The affinities of both groups of compounds for the CB1and CB2receptors were determined and several of them were evaluated in vivo in the mouse. The effects of these substituents on receptor affinities and in vivo activity are discussed and structure–activity relationships are presented. Although many of these compounds are selective for the CB2receptor, only three JWH-423, 1-propyl-3-(4-iodo-1-naphthoyl)indole, JWH-422, 2-methyl-1-propyl-3-(4-iodo-1-naphthoyl)indole, the 2-methyl analog of JWH-423 and JWH-417, 1-pentyl-3-(8-iodo-1-naphthoyl)indole, possess the desirable combination of low CB1affinity and good CB2affinity.