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首页> 外文期刊>European Journal of Medicinal Chemistry: Chimie Therapeutique >Synthesis and dopamine transporter binding of 2beta-isopropyl ester analogs of cocaine.
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Synthesis and dopamine transporter binding of 2beta-isopropyl ester analogs of cocaine.

机译：可卡因的2β-异丙基酯类似物的合成和多巴胺转运蛋白结合。

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摘要

A series of 2beta-isopropyl ester analogs of cocaine (7-11) was synthesised and evaluated in an in vitro dopamine transporter (DAT) binding assays. Ecgonine HCl (5) was obtained from (-)-cocaine (1) by hydrolysis using 1 N HCl. Acid catalysed esterification of 5 using 2-propanol and HCl gas afforded 2beta-isopropyl ecgonine (6). Compounds 7-9 were obtained via esterification of the 3beta-hydroxyl group of 6 using the appropriate acid chloride. Compound 10 was obtained via selective hydrolysis and re-esterification of 7 using 2-propanol and HCl gas. Compound 11 was obtained by reduction of 9 using H(2)/Pd-C. Compounds 7, 10 and 11 showed high binding affinity to the DAT (as indicated from the inhibition of the binding of [(3)H]WIN 35,428 (3)) with IC(50) values (mean +/- S.E.M.) 208.5 +/- 9.5, 47.43 +/- 1.79 and 11.25 +/- 3.37 nM, respectively). Compound 7 is comparatively as active as cocaine, 10 is ca. fivefold more active than cocaine and 11 is ca. 20-fold more active than cocaine and even twice more active than the radioligand 3. Compound 11, like its methyl ester analog (2' aminococaine), exhibited the highest affinity to the DAT. These results, along with previous results, emphasise the importance of a hydrogen-bond donor group at the 2'-position of cocaine and its isopropyl ester analogs to enhance binding affinity to the DAT.
机译：合成了一系列可卡因的2β-异丙基酯类似物（7-11），并在体外多巴胺转运蛋白（DAT）结合测定中进行了评估。通过使用1 N HCl水解，从（-）-可卡因（1）中获得了盐酸依贡碱（5）。使用2-丙醇和HCl气体对5进行酸催化酯化，得到2β-异丙基芽子碱（6）。通过使用适当的酰氯将6的3β-羟基酯化，获得化合物7-9。通过使用2-丙醇和HCl气体选择性水解和再酯化7，获得化合物10。通过使用H（2）/ Pd-C还原9得到化合物11。化合物7、10和11对DAT具有很高的结合亲和力（如抑制[[3] H] WIN 35,428（3）的结合所示），IC（50）值（平均值+/- SEM）为208.5 +分别为9.5、47.43 +/- 1.79和11.25 +/- 3.37 nM。化合物7具有与可卡因同等的活性，化合物10具有约可卡因的活性。活性比可卡因高五倍，大约是11。活性比可卡因高20倍，甚至比放射性配体3高两倍。化合物11，如其甲酯类似物（2'氨基可卡因），对DAT的亲和力最高。这些结果与先前的结果一起强调了可卡因及其异丙基酯类似物2'-位的氢键供体基团对于增强与DAT的结合亲和力的重要性。

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