2-carbomethoxy-3-aryl-8-bicyclo[3.2.1]octanes: Potent non-nitrogen inhibitors of monoamine transporters

Cocaine is a potent central nervous system stimulant with severe addiction liability. Its reinforcing and stimulant properties derive from inhibition of monoamine transport systems, in particular the dopamine transporter (DAT ). This inhibition results in an increase in synaptic dopamine with subsequ ent stimulation of postsynaptic dopamine receptors. A wide variety of ligan ds manifest potent inhibition of the DAT, and these ligands include 3-arylt ropane as well as 8-oxa-3-aryltropane analogues of cocaine. There has been considerable effort to determine structure-activity relationships of cocain e and congeners, and it is becoming clear that these inhibitors do not all interact with the DAT in the same manner. The functional role of the 8-hete roatom is the focus of this study. We describe the preparation and biology of a series of 2-carbomethoxy-3-arylbicyclo[3.2.1]octane analogues. Results show that methylene substitution of the amine or ether function of the 8-h etero-2-carbomethoxy-3-arylbicyclo[3.2.1]octanes yields potent inhibitors o f monoamine transport. Therefore neither nitrogen nor oxygen are prerequisi tes for binding of tropane-like ligands to monoamine transporters.