Novel 3-aminomethyl- and 4-aminopiperidine analogues of 1-[2-(diphenylmethoxy)ethyl]-4-(3-phenylpropyl)piperazines: Synthesis and evaluation as dopamine transporter ligands

We have undertaken a program to develop cocaine antagonists based on the pr emise that such compounds should block cocaine binding but permit reuptake of dopamine at the dopamine transporter (DAT). To evaluate the structural f eatures of potential cocaine antagonists, 3-aminomethylpiperidine and 4-ami nopiperidine moieties were incorporated at the central bridge region (piper azine ring) of GBR 12935. The compounds were assayed as inhibitors of [I-12 5]RTI-55 binding at the DAT and monoamine transport. The results indicated that most of the new compounds preferentially inhibited norepinephrine reup take by its transporter (NET) but in some cases retained binding selectivit y for the DAT. In general, the binding selectivity and potency of [H-3]NE r euptake inhibition were very sensitive to modifications of the central brid ge diamine moiety (position of two basic nitrogen atoms). Compound 6 exhibi ted the highest ratio (14-fold) of DA reuptake inhibition to RTI-55 binding inhibition at the DAT; however, in an in vitro assay of cocaine antagonism , this compound failed to reduce inhibition of [H-3]DA uptake by cocaine. T hese results demonstrated that separation of biological activities into the binding and reuptake inhibition can be achieved by alterations in the inte rnal diamine component of GBR 12935, but additional modifications are neces sary before these agents constitute lead compounds for development as cocai ne antagonists.