title: 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.
abstract: 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.
authors.affiliation: Laboratory of Medicinal Chemistry, Building 8, Room B1-23, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: D B
authors.initials: DB
authors.lastname: Lewis
authors.forename: D
authors.initials: D
authors.lastname: Matecka
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.forename: L W
authors.initials: LW
authors.lastname: Hsin
authors.forename: C M
authors.initials: CM
authors.lastname: Dersch
authors.forename: D
authors.initials: D
authors.lastname: Stafford
authors.forename: J R
authors.initials: JR
authors.lastname: Glowa
authors.forename: R B
authors.initials: RB
authors.lastname: Rothman
authors.forename: K C
authors.initials: KC
authors.lastname: Rice
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D019970:Cocaine-Related Disorders / Q000188:drug therapy*; D003692:Delayed-Action Preparations; D004298:Dopamine / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors / Q000138:chemical synthesis*; D006900:Hydroxylation; D008024:Ligands; D008253:Macaca mulatta; D008297:Male; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D008745:Methylation; D015394:Molecular Structure; D009419:Nerve Tissue Proteins; D010100:Oxygen / Q000737:chemistry; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D014316:Tritium
chemical_list: C402278:1-(2-(bis(4--fluorophenyl)methoxy)ethyl)-4-(3-hydroxy-3-phenylpropyl)piperazine decanoate; C402277:1-(2-(bis(4-fluorophenyl)--methoxy)ethyl)-4-(3-hydroxy-3-phenylpropyl)piperazine; D002352:Carrier Proteins; D003692:Delayed-Action Preparations; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D008024:Ligands; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D010879:Piperazines; C493216:Slc6a3 protein, rat; D014316:Tritium; C043425:vanoxerine; C044630:1-(2 (diphenylmethoxy)ethyl)-4-(3-phenylpropyl)piperazine; D010100:Oxygen; D004298:Dopamine