Two-and Three Dimensional Combinatorial Chemistry from Multicomponent Grignard Reagents

摘要

The conjugate addition of five component Grignard reagents to methyl ecgonidine was used to create libraries of 3-substituted tropanes.By variation in the reagent combination in 10 such 5-membered sublibraries,a library of 25 compounds was made in a two-dimensional format.Screening of this library led to identification of two new potent monoamine transporter ligands that were subsequently synthesized.The most potent compound in this library was (lR,2S,3S,5S)-3-(3,4-dimethylphenyl)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylic acid methyl ester,which inhibited dopamine transporter (hDAT) binding and reuptake with a K_i of 26 and 20 nM,respectively.The conjugate addition to a 5-membered library of methyl ecgonidine analogues with variation of nitrogen substituent was also carried out and used to create 15 sublibraries of 25 compounds,which displayed 125 compounds in a three-dimensional format.From this 3D library,several potent dopamine transport inhibitors were likewise identified and synthesized.The most potent hDAT inhibitor discovered was (lR,2S,3S,5S)-3-(3,4-dimethylphenyl)-8-pentyl-8-azabicyclo[3.2.1]octane-2-carboxylic acid methyl ester.The study also showed that 3-alkyltropanes were poor inhibitors of monoamine transporters.