Two- and three dimensional combinatorial chemistry from multicomponent Grignard reagents.
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 (1R,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 (1R,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.
Bülow
Anne
A
Department of Chemistry, University of Aarhus, Langelandsgade 140, DK-8000 Aarhus C, Denmark.
Sinning
Steffen
S
Wiborg
Ove
O
Bols
Mikael
M
D000438:Alcohols / Q000737:chemistry; D003042:Cocaine / Q000138:chemical synthesis / Q000737:chemistry; D020650:Combinatorial Chemistry Techniques / Q000379:methods*; D050483:Dopamine Plasma Membrane Transport Proteins; D004987:Ethers / Q000737:chemistry; D008401:Gas Chromatography-Mass Spectrometry; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D049990:Membrane Transport Modulators; D026901:Membrane Transport Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D008745:Methylation; D015394:Molecular Structure; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D011804:Quinolines / Q000737:chemistry; D014326:Tropanes / Q000138:chemical synthesis* / Q000737:chemistry*
D000438:Alcohols; D050483:Dopamine Plasma Membrane Transport Proteins; D004987:Ethers; D008562:Membrane Glycoproteins; D049990:Membrane Transport Modulators; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D011804:Quinolines; D014326:Tropanes; C120357:ecgonidine; C037219:quinoline; D003042:Cocaine