Synthesis and ligand binding of η⁶-(2β-carbomethoxy-3β-phenyltropane) transition metal complexes

The transition metal complexes [η⁶-(2β-carbomethoxy-3β- phenyltropane)]tricarbonylchromium (3) and [η⁶-(2β-carbomethoxy-3β- phenyltropane)][η⁵-(pentamethylcyclopentadienyl)]ruthenium(II) triflate (4) were synthesized from 2β-carbomethoxy-3β-phenyltropane (2, WIN 35,065) to further elucidate the influence of substituents on the 3β-aryl on the affinity of the ligand for cocaine-binding sites at the dopamine transporter. The compounds were tested for their ability to displace bound [³H]WIN 35,428 (5) from rat caudate putamen tissue and for their ability to inhibit [³H]dopamine uptake. The binding affinity for 3 was 2-fold greater than those observed for cocaine (1) and 2, while the binding affinity for 4 was found to be 100-fold less than those of 1 and 2. In addition, 3 was equipotent with 1 and 2 in [³H]dopamine uptake inhibition studies, while 4 was 10-fold less potent. The potencies of the complexes 3 and 4 correlated well with the structure-activity relationships of other 2β-carbomethoxy- 3β-aryltropane derivatives. These data further support a pharmacophore model in which the region occupied by the aryl ring is a lipophilic pocket with electropositive character.