NOVEL 2-SUBSTITUTED COCAINE ANALOGS - UPTAKE AND LIGAND-BINDING STUDIES AT DOPAMINE, SEROTONIN AND NOREPINEPHRINE TRANSPORT SITES IN THE RAT-BRAIN

A novel scheme utilizing vinylcarbenoid precursors has been developed for the synthesis of tropane analogs of cocaine. Specificities of thes e compounds for dopamine (DA), serotonin (5-HT) or norepinephrine (NE) transporters were determined by both uptake inhibition and binding as says. In each of the analogs, the aryl group at position 3 was bound d irectly to the tropane ring (as in WIN-35,428), and methyl or ethyl ke tone moieties were present at position 2 in lieu of the ester linkage present in cocaine. The addition of methyl or ethyl ketone groups in p osition 2 did not affect potency compared to ester groups in the same position, but substituents on the benzene ring greatly affected potenc ies. The analogs could be categorized according to their relative spec ificity, which consisted of those selective for DA and NE transporters with little affinity for the 5-HT transporter (e.g., WF-39), those se lective for only the DA transporter (e.g., WF-29) and those selective for the 5-HT transporter (e.g., WF-31) with much less affinity for the DA and NE transporters. There also were those analogs (e.g., WF-23) w ith high affinity, but with equal affinity at all three transporters. The analogs displayed significant correlation between uptake inhibitio n and binding displacement at DA, 5-HT and NE transport sites. These r esults suggest that large variations in the tropane structure do not r esult in a differentiation between binding at biogenic amine transport ers and inhibition of amine uptake.