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

被引:66
作者
Hsin, LW
Dersch, CM
Baumann, MH
Stafford, D
Glowa, JR
Rothman, RB
Jacobson, AE
Rice, KC
机构
[1] NIDDKD, Med Chem Lab, NIH, Bethesda, MD 20892 USA
[2] NIDA, Clin Psychopharmacol Sect, IRP, NIH, Baltimore, MD 21224 USA
[3] Louisiana State Univ, Med Ctr, Dept Pharmacol & Therapeut, Shreveport, LA 71130 USA
关键词
D O I
10.1021/jm010430f
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
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 enantioniers 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-(dipbenylmethoxy)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.
引用
收藏
页码:1321 / 1329
页数:9
相关论文
共 40 条