DEVELOPMENT OF NOVEL, POTENT, AND SELECTIVE DOPAMINE REUPTAKE INHIBITORS THROUGH ALTERATION OF THE PIPERAZINE RING OF PHENYLMETHOXY)ETHYL]-4-(3-PHENYLPROPYL)PIPERAZINES AND HENYL)METHOXY]ETHYL]-4-(3-PHENYLPROPYL)PIPERAZINES (GBR-12935 AND GBR-12909)

The design, synthesis, and biological evaluation of compounds related to the dopamine (DA) uptake inhibitors: iphenylmethoxy)ethyl]-4-(3-phe nylpropyl)piperazine (1) and -(4-fluorophenyl)methoxy]ethyl]-4-(3-phen ylpropyl) piperazine (2) (GBR 12395 and GBR 12909, respectively), dire cted toward the development and identification of new ligands interact ing with high potency and selectivity at the dopamine transporter (DAT ) is reported. The substitution of the piperazine ring in the GBR stru cture with other diamine moieties resulted in the retention of the hig h affinity of new ligands for the DAT. Some of the modified GBR analog s (e.g. 8, 10, (-)-49, or (-)-50) displayed substantially higher selec tivity (4736- to 693-fold) for the dopamine (DA) versus the serotonin (5HT) reuptake site than the parent compounds. The bis(p-fluoro) subst itution in the (diphenylmethoxy)ethyl fragment slightly increased the affinity of the ligands at the DA reuptake site but reduced their sele ctivity at this site (e.g. 9 and 8, 11 and 10, or 17 and 16, respectiv ely). Congeners, such as the series of monosubstituted and symmetrical ly disubstituted piperazines and trans-2,5-dimethylpiperazines, which lack the (diphenylmethoxy)ethyl substituent lost the affinity for the DAT yet exhibited very high potency for binding to the a receptors (e. g. 28). The chiral pyrrolidine derivatives of 1, (-)-49, and (+)-49, e xhibited an enantioselectivity ratio of 181 and 146 for the inhibition of DA reuptake and binding to the DAT, respectively.