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 it s propensity to bind to monoamine transporter systems. It has generall y been assumed t;hat the amino function on monoamines is a requirement for binding to monoamine transporters. In particular, the 8-amino fun ction on the tropane skeleton of cocaine and cocaine analogs has been assumed to provide an ionic bond to the aspartic acid residue on the d opamine 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 ar e particularly potent (IC50 = 3.27 and 2.34 nM, respectively) inhibito rs of the dopamine transporter. We now describe the synthesis and biol ogy 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.