用于阿片样物质活性的3-氨基丙酰基取代芬太尼类似物的合成与评价
Synthesis and evaluation of 3-aminopropionyl substituted fentanyl analogues for opioid activity.
作者信息
Petrov Ravil R, Vardanyan Ruben S, Lee Yeon S, Ma Shou-wu, Davis Peg, Begay Lucinda J, Lai Josephine Y, Porreca Frank, Hruby Victor J
机构信息
Department of Chemistry, University of Arizona, Tucson, AZ 85721, USA.
出版信息
Bioorg Med Chem Lett. 2006 Sep 15;16(18):4946-50. doi: 10.1016/j.bmcl.2006.06.040. Epub 2006 Jul 7.
Abstract
An enkephalin analogue coupled to 'aminofentanyl' has been synthesized and tested for biological activities at the mu and delta opioid receptors. Aminofentanyl which represents a structural derivative of fentanyl has been synthesized by acylation of 1-(2-phenethyl)-4-(N-anilino)piperidine with phthaloyl protected beta-alaninyl chloride in the presence of DIPEA, followed by deprotection with hydrazine hydrate. Aminofentanyl has also been successfully acylated with ethyl isocyanate, various acid anhydrides, to further investigate structure-activity relationships of these new fentanyl derivatives. Among the new derivatives compound 7 which carries a Tyr-D-Ala-Gly-Phe opioid message sequence showed good opioid affinity (1 nM at both delta and mu opioid receptors) and bioactivity (34.9 nM in MVD and 42 nM in GPI/LMMP bioassays).
摘要
一种与“氨基芬太尼”偶联的脑啡肽类似物已被合成，并在μ和δ阿片受体上测试了其生物活性。代表芬太尼结构衍生物的氨基芬太尼是通过在二异丙基乙胺（DIPEA）存在下，用邻苯二甲酰保护的β-丙氨酰氯对1-(2-苯乙基)-4-(N-苯胺基)哌啶进行酰化反应，然后用水合肼脱保护而合成的。氨基芬太尼也已成功地用异氰酸乙酯、各种酸酐进行酰化，以进一步研究这些新型芬太尼衍生物的构效关系。在新衍生物中，带有Tyr-D-Ala-Gly-Phe阿片信息序列的化合物7显示出良好的阿片亲和力（在δ和μ阿片受体上均为1 nM）和生物活性（在MVD生物测定中为34.9 nM，在GPI/LMMP生物测定中为42 nM）。
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