We have recently described efforts directed toward delineating structure-activity relationships for cocaine in an effort to identify a possible antagonist of cocaine's action at the dopamine re-uptake transporter. During these efforts we discovered that this cocaine-recognition site is rather promiscuous in its ability to accept groups substantially different from cocaine's C-2 carbomethoxy substituent. The carbethoxyisoxazole 1, for example, was found to be about 2-fold more potent than cocaine in both [3H]mazindol binding and [3H]dopamine uptake studies. This finding and others made us question the idea that specific hydrogen bond donor groups are present within the cocaine recognition site for binding to the carbomethoxy group (Figure 1). To explore this point further, we chose to investigate the activity of the four new cocaine analogues, 2a-d, in which the C-2 ester group was replaced by a vinyl group incapable of any strong hydrogen bonding.