Kline R H, Wright J, Eshleman A J, Fox K M, Eldefrawi M E
Department of Biomedicinal Chemistry, University of Maryland, Baltimore 21201.
J Med Chem. 1991 Feb;34(2):702-5. doi: 10.1021/jm00106a035.
Five (1R-2-exo-3-exo)-3-(N-phenylcarbamoyl)ecgonine methyl ester analogues were synthesized and characterized by 1H and 13C NMR, IR, and thermospray MS. The compounds were synthesized in two or three steps as (-)-stereoisomers from (-)-ecgonine in good yield (56% overall). These cocaine derivatives were assessed for their ability to inhibit [3H]cocaine binding to rat striatal tissue and to inhibit [3H]dopamine uptake into synaptosomes prepared from the same tissue. The most potent of the analogues was (1R-2-exo-3-exo)-2-(carbomethoxy)-8-methyl-8-azabicyclo[3.2.1]octyl 3-N-(3'-nitrophenyl)carbamate. IC50 values for inhibition of cocaine binding and dopamine uptake were 37 and 178 nM, respectively. Amino derivatives were less active than the nitro and (1R-2-exo-3-exo)-2-(carbomethoxy)-8-methyl-8-azabicyclo [3.2.1]octyl 3-N-(4'-aminophenyl)carbamate had the lowest affinity for the receptor with IC50 values of 63 and greater than 100 microM in the aforementioned assays, respectively.
合成了五种(1R - 2 - exo - 3 - exo)-3-(N - 苯基氨基甲酰基)芽子碱甲酯类似物，并通过1H和13C NMR、IR以及热喷雾质谱对其进行了表征。这些化合物以(-)-芽子碱为原料，通过两步或三步反应合成(-)-立体异构体，产率良好（总体产率为56%）。对这些可卡因衍生物抑制[3H]可卡因与大鼠纹状体组织结合以及抑制[3H]多巴胺摄取到由相同组织制备的突触体中的能力进行了评估。最有效的类似物是(1R - 2 - exo - 3 - exo)-2-(甲氧基羰基)-8 - 甲基 - 8 - 氮杂双环[3.2.1]辛基3 - N-(3'-硝基苯基)氨基甲酸酯。抑制可卡因结合和多巴胺摄取的IC50值分别为37 nM和178 nM。氨基衍生物的活性低于硝基衍生物，(1R - 2 - exo - 3 - exo)-2-(甲氧基羰基)-8 - 甲基 - 8 - 氮杂双环[3.2.1]辛基3 - N-(4'-氨基苯基)氨基甲酸酯对受体的亲和力最低，在上述测定中的IC50值分别为63 nM和大于100 μM。
