The definition of the pharmacophore for the cocaine (la) binding site on the dopamine transporter has been the subject of considerable scientific interest for the last few year~.l-~ A number of 3/3-(substituted phenyl) tropane-2/3-carboxylic acid esters (lb) have been synthesized as potential ligands for this binding site and evaluated for their ability to inhibit [3HlWIN 35,428 binding at the dopamine transporter. The results show that substituents on the 3/3-aromatic ring greatly influence binding potency at the dopamine transporter and that the nature of the 2/3-substituents plays a key role in determining the selectivity for the dopamine transporter relative to the norepinephrine and serotonin transporters. For example, whereas methyl esters show little transporter selectivity, phenyl esters are highly selective for the dopamine transp0rter.lBioisosterism is an important concept which serves as a valuable aid in structure-activity relationship studies and new drug design.l0Jl In our studies to characterize the pharmacophore for the cocaine binding site on the dopamine transporter, we had found that 3/34 4'-chlorophenyl)-2/3-(3-phenyl-1',2',4'-oxadiazol-5' y1)tropane (3, RTI-130) had high binding potency at the dopamine transporter, and since the oxadiazole function is stable to chemical and enzymic degradation, this ligand was an excellent, stable bioisostere for 3/3-(4' chlorophenyl)tropane-2/3-carboxylic acid phenyl ester (2, RTI-113).12-14 In our studies to further define the requirements of the cocaine binding site, we examined analogues of 3 possessing other 5-membered heterocyclic rings in the 2fi-position. We describe in this paper the synthesis of 3/3-(4'-chlorophenyl)-2/3-(3'-phenylisoxazol-5'-y1)tropane (4, RTI-1771, 3/3-(4'-chlorophenyl)-2/3-(5' phenyl-1',3',4'-oxadiazol-2'-yl)tropane (5, RTI-188), and 3/34 4'-chlorophenyl)-2/3-(5'-phenyloxazol-2'-yl)tropane (6, RTI-189) and report that 4 is potent and more selective than 3 for the dopamine transporter.