Davies H M, Kuhn L A, Thornley C, Matasi J J, Sexton T, Childers S R
Department of Chemistry, State University of New York at Buffalo 14260-3000, USA.
J Med Chem. 1996 Jun 21;39(13):2554-8. doi: 10.1021/jm9600508.
A novel entry to tropane analogs of cocaine was developed based on the reaction of rhodium-stabilized vinylcarbenoids with pyrroles. These analogs were tested in binding to dopamine, serotonin (5-HT), and norepinephrine transporters in membranes from rat striatum and frontal cortex. In all the analogs, the aryl group at the 3 position was directly bound to the tropane ring and an ethyl ketone moiety was present at the 2 position. By appropriate modification of the aryl and nitrogen substituents, highly potent and 5-HT selective tropanes were prepared. The most potent and selective compound was 3 beta-[4-(1-methylethenyl)phenyl]-2 beta-propanoyl-8-azabicyclo[3.2.1]octane (13b) which had a Ki of 0.1 nM at 5-HT transporters and was 150 times more potent at 5-HT vs dopamine transporters and almost 1000 times more potent at 5-HT vs norepinephrine transporters.
基于铑稳定的乙烯基卡宾与吡咯的反应，开发了一种合成可卡因托烷类似物的新方法。对这些类似物进行了测试，以检测它们与大鼠纹状体和额叶皮质膜中多巴胺、5-羟色胺（5-HT）和去甲肾上腺素转运体的结合情况。在所有类似物中，3位的芳基直接与托烷环相连，2位存在一个乙基酮部分。通过对芳基和氮取代基进行适当修饰，制备出了高效且对5-HT具有选择性的托烷。最有效且选择性最强的化合物是3β-[4-(1-甲基乙烯基)phenyl]-2β-丙酰基-8-氮杂双环[3.2.1]辛烷（13b），它对5-HT转运体的Ki值为0.1 nM，对5-HT转运体的效力是多巴胺转运体的150倍，是去甲肾上腺素转运体的近1000倍。
