A series of 4'-substituted 3beta-phenyltropane-2beta-carboxylic acid methyl esters were synthesized and evaluated for binding at the dopamine transporter (DAT) in order to better define the pharmacophore for the cocaine binding site on the DAT. Results from the study of 3beta-[(4'-phenylalkyl)phenyl]tropane-2beta-carboxylic acid methyl esters (5a-c and 6a,b) revealed strong evidence of a previously unknown remote binding domain. The 3beta-[(4'-phenylethyl)phenyl]tropane-2beta-carboxylic acid methyl ester (5a), which has a two methylene linker between the 3beta-phenyl group and the remote phenyl group, has an IC(50) value of 5.14 nM at the DAT. The 3beta-[4'-(benzyl)phenyl] and 3beta-[4'-(phenylpropyl)phenyl] analogues 6b and 5b, respectively, are 102- and 68-fold less potent than 5a at the DAT. Compound 5a also has good affinity for the serotonin and norepinephrine transporters (K(i) = 21 and 6.5 nM, respectively) and is thus a nonselective monoamine uptake inhibitor. Electrostatic effects make a significant contribution to the DAT binding affinity of the 3beta-[(4'-phenylalkenyl)phenyl]tropane-2beta-carboxylic methyl esters (6c, 7a,b, and 8) and 3beta-[(4'-phenylalkynl)phenyl]tropane-2beta-carboxylic acid methyl esters (4a-e). However, the results from the DAT binding on these compounds suggest that there may be another binding domain even further remote from the 4'-position on the 3beta-phenyl group. In both cases, steric barriers have to be overcome before potent binding to the DAT is observed. 3beta-(4'(3-Phenyl-1-propynyl)phenyl)tropane-2beta-carboxylic acid methyl ester (4b), with an IC(50) value of 1.82 nM, was the most potent compound studied. This compound possessed K(i) values of 1.19 and 16.5 nM for the serotonin and norepinephrine transporter and is thus a nonselective monoamine uptake inhibitor.