Heteroaromatic analogs of 1-[2-(diphenylmethoxy)ethyl]- and 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazines (GBR 12935 and GBR 12909) as high-affinity dopamine reuptake inhibitors

被引:63
作者
Matecka, D
Lewis, D
Rothman, RB
Dersch, CM
Wojnicki, FHE
Glowa, JR
DeVries, AC
Pert, A
Rice, KC
机构
[1] NIDDKD, MED CHEM LAB, NIH, BETHESDA, MD 20892 USA
[2] NIDA, ADDICT RES CTR,IRP,CLIN PSYCHOPHARMACOL SECT,NIH, BALTIMORE, MD 21224 USA
[3] NIMH, BIOL PSYCHIAT BRANCH, NIH, BETHESDA, MD 20892 USA
关键词
D O I
10.1021/jm9606599
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
A new series of heteroaromatic GBR 12935 [1-[2-(diphenylmethoxy)ethyl]-4-(3-phenylpropyl)-piperazine] (1) and GBR 12909 [1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)-piperazine] (2) analogs was synthesized and evaluated as dopamine transporter (DAT) ligands. Analogs 5-16, in which the benzene ring in the phenylpropyl side chain of the GBR molecule had been replaced with a thiophene, furan, or pyridine ring, exhibited high affinity and selectivity for the DAT vs serotonin transporter (SERT) and stimulated locomotor activity in rats in a manner similar to the parent compound 2. In cocaine and food self-administration studies in rhesus monkeys, both thiophene-containing (6 and 8) and pyridine-containing (14 and 16) derivatives displayed potency comparable to 2 in decreasing the cocaine-maintained responding at the doses tested (0.3, 1.7, and 3 mg/kg). However, these compounds did not produce the degree of separation between food- and cocaine-maintained responding that was seen with 2. Among the bicyclic fused-ring congeners 17-38, the indole-containing analog of 2, 22, showed the greatest affinity for binding to the DAT, with IC50 = 0.7 nM, whereas the corresponding indole-containing derivative of 1, 21, displayed the highest selectivity (over 600-fold) at this site vs the SEPT site.
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页码:705 / 716
页数:12
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