| Abstract
| - An investigation into the preparation of potential extended-release cocaine-abuse therapeuticagents 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, andevaluated for their ability to bind to the dopamine transporter (DAT) and to inhibit the uptakeof [3H]-labeled dopamine (DA). The addition of hydroxy and methoxy substituents to the benzenering on the phenylpropyl moiety of 1a−1d resulted in a series of potent and selective ligandsfor 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 sidechain provided ketones 29 and 30, which demonstrated greatly reduced affinity for the DATand decreased potency in inhibiting the uptake of [3H]DA, and benzylic alcohols 31−36, whichwere highly potent and selective at binding to the DAT and inhibiting [3H]DA uptake. Theenantiomers 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 inmonkeys without affecting behaviors maintained by food, with 34 and 36 equipotent to eachother and both more potent in behavioral tests than the parent compound 1b. Intramuscularinjections of compound 41 (the decanoate ester of racemate 32) eliminated cocaine-maintainedbehavior for about a month following one single injection, without affecting food-maintainedbehavior. The identification of analogues 32, 34, and 36, thus, provides three potentialcandidates for esterification and formulation as extended-release cocaine-abuse therapeuticagents.
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