Secondary amine analogues of 3 beta-(4'-substituted phenyl)tropane-2 beta-carboxylic acid esters and N-norcocaine exhibit enhanced affinity for serotonin and norepinephrine transporters.

N-Norcocaine (2) and six N-nor-3 beta-(4'-substituted phenyl)tropane-2 beta-carboxylic acid esters (4a-f) were synthesized by N-demethylation of cocaine (1) and the appropriate 3 beta-(substituted phenyl)-tropane analogues (3a-f) with alpha-chloroethyl chloroformate. Radioligand binding affinities of 2 and 4a-f at the DA, 5-HT, and NE transporter were measured and compared to those of 1 and 3a-f. N-Demethylation produced relatively small effects at the DA transporter. In contrast, 4-19-fold and 2-44-fold enhanced affinity at the serotonin and norepinephrine transporter resulted from demethylation. N-Nor-3 beta-(4'-iodophenyl)tropane-2 beta-carboxylic acid methyl ester (4d) with an IC50 = 0.36 nM showed the greatest affinity for the serotonin transporter. However, N-nor-3 beta-(4'-ethylphenyl)tropane-2 beta-carboxylic acid methyl ester (4e) showed the greatest selectivity for the serotonin transporter.