Oxygenated analogues of 1-[2-(diphenylmethoxy)ethyl]- and 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazines (GBR 12935 and GBR 12909) as potential extended-action cocaine-abuse therapeutic agents

An investigation into the preparation of potential extended-release cocaine -abuse therapeutic agents afforded a series of compounds related to 1-[2-(d iphenylmethoxy)ethyl]-4-(3-phenylpropyl) piperazine(1a) and 1-[2-[bis(4-flu orophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine (1b) (GBR 12935 and G BR 12909, respectively), which were designed, synthesized, and evaluated fo r their ability to bind to the dopamine transporter (DAT) and to inhibit th e uptake of [H-3]-labeled dopamine (DA). The addition of hydroxy and methox y substituents to the benzene ring on the phenylpropyl moiety of 1a-1d resu lted in a series of potent and selective ligands for the DAT (analogues 5-2 8). The hydroxyl groups were included to incorporate a medium-chain carboxy lic acid ester into the molecules, to form oil-soluble prodrugs, amenable t o "depot" injection techniques. The introduction of an oxygen-containing fu nctionality to the propyl side chain provided ketones 29 and 30, which demo nstrated greatly reduced affinity for the DAT and decreased potency in inhi biting the uptake of [H-3]DA, and benzylic alcohols 31-36, which were highl y potent and selective at binding to the DAT and inhibiting [H-3]DA uptake. The enantiomers of 32 (34 and 36) were practically identical in biological testing. Compounds Ib, 32, 34, and 36 all demonstrated the ability to decr ease cocaine-maintained responding in monkeys without affecting behaviors m aintained by food, with 34 and 36 equipotent to each other and both more po tent in behavioral tests than the parent compound Ib. Intramuscular injecti ons of compound 41 (the decanoate ester of racemate 32) eliminated cocaine- maintained behavior for about a month following one single injection, witho ut affecting food-maintained behavior. The identification of analogues 32, 34, and 36, thus, provides three potential candidates for esterification an d formulation as extended-release cocaine-abuse therapeutic agents.