2-Carbomethoxy-3-aryl-8-oxabicyclo[3.2.1]octanes: potent non-nitrogen inhibitors of monoamine transporters.
Cocaine is a potent stimulant of the mammalian central nervous system. Its reinforcing and stimulant properties have been associated with its propensity to bind to monoamine transporter systems. It has generally been assumed that the amino function on monoamines is a requirement for binding to monoamine transporters. In particular, the 8-amino function on the tropane skeleton of cocaine and cocaine analogs has been assumed to provide an ionic bond to the aspartic acid residue on the dopamine transporter (DAT). We have prepared the first 8-oxa analogs of the 3-aryltropanes (WIN compounds) and have found that the 3 beta-(3,4-dichlorophenyl) (6g) and 3 alpha-(3,4-dichlorophenyl) (7g) analogs are particularly potent (IC50 = 3.27 and 2.34 nM, respectively) inhibitors of the dopamine transporter. We now describe the synthesis and biology of the family of 2-carbomethoxy-3-aryl-8-oxabicyclo[3.2.1]octanes and demonstrate that an amino nitrogen is not required for binding to the DAT.
Meltzer
P C
PC
Organix Inc., Woburn, Massachusetts 01801, USA.
Liang
A Y
AY
Blundell
P
P
Gonzalez
M D
MD
Chen
Z
Z
George
C
C
Madras
B K
BK
D000818:Animals; D001667:Binding, Competitive; D001692:Biological Transport; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D002421:Caudate Nucleus / Q000378:metabolism; D015283:Citalopram / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors / Q000138:chemical synthesis* / Q000378:metabolism; D005260:Female; D008024:Ligands; D008252:Macaca fascicularis; D008297:Male; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors*; D026901:Membrane Transport Proteins; D008956:Models, Chemical; D008958:Models, Molecular; D009419:Nerve Tissue Proteins; D009795:Octanes / Q000737:chemistry*; D011699:Putamen / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins; D013329:Structure-Activity Relationship; D014326:Tropanes / Q000737:chemistry*
D002352:Carrier Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D008024:Ligands; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D009795:Octanes; D050486:Serotonin Plasma Membrane Transport Proteins; D014326:Tropanes; D015283:Citalopram