An investigation into the preparation of potential extended-release
cocaine-abuse therapeutic agents afforded a series of compounds related to 1-[2-(diphenylmethoxy)ethyl]-4-(3-phenylpropyl)
piperazine (1a) and 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)
piperazine (1b) (
GBR 12935 and
GBR 12909, respectively), which were designed, synthesized, and evaluated for their ability to bind to the
dopamine transporter (DAT) and to inhibit the uptake of [(3)H]-labeled
dopamine (DA). The addition of hydroxy and methoxy substituents to the
benzene ring on the phenylpropyl moiety of 1a-1d resulted in a series of potent and selective
ligands for the DAT (analogues 5-28). The
hydroxyl groups were included to incorporate a medium-chain
carboxylic acid ester into the molecules, to form oil-soluble
prodrugs, amenable to "depot" injection techniques. The introduction of an
oxygen-containing functionality to the propyl side chain provided
ketones 29 and 30, which demonstrated greatly reduced affinity for the DAT and decreased potency in inhibiting the uptake of [(3)H]DA, and benzylic
alcohols 31-36, which were highly potent and selective at binding to the DAT and inhibiting [(3)H]DA uptake. The enantiomers of 32 (34 and 36) were practically identical in
biological testing. Compounds 1b, 32, 34, and 36 all demonstrated the ability to decrease
cocaine-maintained responding in monkeys without affecting behaviors maintained by food, with 34 and 36 equipotent to each other and both more potent in behavioral tests than the parent compound 1b.
Intramuscular injections of compound 41 (the decanoate
ester of racemate 32) eliminated
cocaine-maintained behavior for about a month following one single injection, without affecting food-maintained behavior. The identification of analogues 32, 34, and 36, thus, provides three potential candidates for esterification and formulation as extended-release
cocaine-abuse therapeutic agents.