title: Development of long-acting dopamine transporter ligands as potential cocaine-abuse therapeutic agents: chiral hydroxyl-containing derivatives of 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine and 1-[2-(diphenylmethoxy)ethyl]-4-(3-phenylpropyl)piperazine.
abstract: In our search for long-acting agents for the treatment of cocaine abuse, a series of optically pure hydroxylated derivatives of 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine (1) and 1-[2-(diphenylmethoxy)ethyl]-4-(3-phenylpropyl)piperazine (2) (GBR 12909 and GBR 12935, respectively) were synthesized and evaluated in vitro and in vivo. The enantiomers of the 2-hydroxylated analogues displayed substantial enantioselectivity. The S enantiomers displayed higher dopamine transporter (DAT) affinity and the R enantiomers were found to interact at the serotonin transporter (SERT) with higher affinity. The two-carbon spacer between the hydroxyl group and the piperazine ring was essential for enantioselectivity, and the length of the alkyl chain between the phenyl group and the piperazine ring influenced binding affinity and selectivity for the DAT and SERT. Phenylethyl analogues had a higher binding affinity for the SERT and a weaker affinity and selectivity for the DAT than the corresponding phenylpropyl analogues. Thus, (S)-(+)-1-[4-[2-[bis(4-fluorophenyl)methoxy]ethyl]piperazinyl]-3-phenylpropan-2-ol (6) displayed the highest affinity to the DAT, and (S)-(+)-1-[4-[2-(diphenylmethoxy)ethyl]piperazinyl]-3-phenylpropan-2-ol (8) had the highest selectivity. The latter (8) is one of the most DAT selective ligands known. In accord with the in vitro data, 6 showed greater potency than 7 in elevating extracellular dopamine levels in a microdialysis assay and in inhibiting cocaine-maintained responding in rhesus monkeys.
authors.affiliation: Laboratory of Medicinal Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Ling-Wei
authors.initials: LW
authors.lastname: Hsin
authors.forename: Christina M
authors.initials: CM
authors.lastname: Dersch
authors.forename: Michael H
authors.initials: MH
authors.lastname: Baumann
authors.forename: David
authors.initials: D
authors.lastname: Stafford
authors.forename: John R
authors.initials: JR
authors.lastname: Glowa
authors.forename: Richard B
authors.initials: RB
authors.lastname: Rothman
authors.forename: Arthur E
authors.initials: AE
authors.lastname: Jacobson
authors.forename: Kenner C
authors.initials: KC
authors.lastname: Rice
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001559:Benzhydryl Compounds / Q000138:chemical synthesis / Q000494:pharmacology; D019970:Cocaine-Related Disorders / Q000188:drug therapy*; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D006801:Humans; D008024:Ligands; D008253:Macaca mulatta; D008297:Male; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins / Q000378:metabolism*; D017551:Microdialysis; D009419:Nerve Tissue Proteins; D010879:Piperazines / Q000138:chemical synthesis* / Q000494:pharmacology*; D020005:Propanols / Q000138:chemical synthesis* / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism
chemical_list: C452424:1-(4-(2-(bis(4-fluorophenyl)methoxy)ethyl)piperazinyl)-3-phenylpropan-2-ol; C452425:1-(4-(2-(diphenylmethoxy)ethyl)piperazinyl)-3-phenylpropan-2-ol; D001559:Benzhydryl Compounds; 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; D020005:Propanols; C493214:SLC6A3 protein, human; C493216:Slc6a3 protein, rat