POTENT AND SELECTIVE LIGANDS FOR THE DOPAMINE TRANSPORTER (DAT) - STRUCTURE-ACTIVITY RELATIONSHIP STUDIES OF NOVEL IPHENYLMETHOXY)ETHYL]-1-(3-PHENYLPROPYL)PIPERIDINE ANALOGS

Molecular structural modifications of iphenylmethoxy)ethyl]-1-(3-pheny lpropyl)piperidine (1a), a dopamine transporter (DAT)-specific ligand, generated several novel analogues. Biological activities of these new molecules for their binding to the DAT and serotonin transporter (SER T) were evaluated in rat striatal membranes. Some of these new analogu es were more potent and selective than GBR 12909 when their binding to the DAT relative to SERT was compared. Thus compounds 9 and 19a were among the most potent (IC50 = 6.6 and 6.0 nM, respectively) and select ive (DAT/SERT = 33.8 and 30.0, respectively) compounds in this series, and they were more active than GBR 12909 (IC50 = 14 nM, DAT/SERT = 6. 1). Introduction of a double bond in the N-propyl side chain of these molecules did not influence their activities to a great extent. Bioiso steric replacement of the aromatic phenyl group by a thiophene moiety produced some of the most potent compounds in this series.