Cocaine and 3β-(4'-substituted phenyl)tropane-2β-carboxylic acid ester and amide analogues. New high-affinity and selective compounds for the dopamine transporter

Article abstract of DOI:10.1021/jm00002a020

Several 2β-carboxylic acid ester and amide analogues of cocaine and of 3β-(4'-substituted phenyl)tropane-2β-carboxylic acid were prepared. The binding affinities of these compounds, and of some previously prepared analogues, at the dopamine (DA), norepinephrine (NE), and serotonin (5-HT) transporters were determined. The phenyl esters of 3β-(4'-methylphenyl)and 3β-(4'-chlorophenyl)tropane-2β-carboxylic acid are highly potent and highly selective for the DA transporter. The isopropyl esters of 3β-(4'- chlorophenyl)- and 3β-(4'-iodophenyl)tropane-2β-carboxylic acid also possess high DA affinity and show significant DA transporter selectivity. Similarly, the phenyl and isopropyl ester analogues of cocaine are much more selective for the DA transporter than cocaine. Tertiary amide analogues of cocaine and of 3β-(4'-substituted phenyl)tropane-2β-carboxylic acids are more potent inhibitors of radioligand binding at the DA transporter than the primary and secondary amide analogues. In particular, 3β-(4'- chlorophenyl)tropane-2β-N-morpholinocarboxamide as well as the 3β-(4'- chlorophenyl)- and 3β-(4'-iodophenyl)tropane-2β-N-pyrrolidinocarboxamides possess high affinity and selectivity for the DA transporter. The N,N- dimethylamide cocaine analogue is the most selective cocaine amide derivative for the DA transporter. High correlation between the inhibition of radioligand binding and inhibition of uptake at the DA, NE, and 5-HT transporter was found for a selected group of analogues. Within this group, one compound, the isopropyl ester of 3β-(4'-iodophenyl)-tropane-2β- carboxylic acid, was found to be more potent in the inhibition of radioligand binding than in the inhibition of DA uptake. Taken together with its high potency and selectivity at the DA transporter, this suggests that this compound may be a lead in the development of a cocaine antagonist.