Piperazines: New Novel, Potent, & Selective Dopamine Reuptake Inhibitors...! (?)

[Richard_smoker]

Development of Novel, Potent, and Selective Dopamine Reuptake Inhibitors through Alteration of the Piperazine Ring of 1-[2-(Diphenylmethoxy)ethyl]- and 1-[2-[Bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazines (GBR 12935 and GBR 12909)

Dorota Matecka, Richard B. Rothman, Lilian Radesca, Brian R. de Costa, Christina M. Dersch, John S. Partilla, Agu Pert, John R. Glowa, Francis H. E. Wojnicki, and Kenner C. Rice*
J. Med. Chem., 39 (24), 4704 -4716, 1996. jm960305h S0022-2623(96)00305-6

Laboratory of Medicinal Chemistry, Building 8, Room B1-23, National Institute of Diabetes and Digestive and Kidney Diseases, and Biological Psychiatry Branch, National Institute of Mental Health, National Institutes of Health, 9000 Rockville Pike, Bethesda, Maryland 20892, and Clinical Psychopharmacology Section, IRP, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland 21224
Received April 24, 1996

Abstract:
The design, synthesis, and biological evaluation of compounds related to the dopamine (DA) uptake inhibitors: 1-[2-(diphenylmethoxy)ethyl]-4-(3-phenylpropyl)piperazine (1) and 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine (2) (GBR 12395 and GBR 12909, respectively), directed toward the development and identification of new ligands interacting with high potency and selectivity at the dopamine transporter (DAT) is reported. The substitution of the piperazine ring in the GBR structure with other diamine moieties resulted in the retention of the high affinity of new ligands for the DAT. Some of the modified GBR analogs (e.g. 8, 10, (-)-49, or (-)-50) displayed substantially higher selectivity (4736- to 693-fold) for the dopamine (DA) versus the serotonin (5HT) reuptake site than the parent compounds. The bis(p-fluoro) substitution in the (diphenylmethoxy)ethyl fragment slightly increased the affinity of the ligands at the DA reuptake site but reduced their selectivity at this site (e.g. 9 and 8, 11 and 10, or 17 and 16, respectively). Congeners, such as the series of monosubstituted and symmetrically 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 receptors (e.g. 28). The chiral pyrrolidine derivatives of 1, (-)-49, and (+)-49, exhibited an enantioselectivity ratio of 181 and 146 for the inhibition of DA reuptake and binding to the DAT, respectively.

Sorry, I don't have access to the full text--must be an obscure journal--however, I thought it might be of interest to those who were previously discussing DAT protein (messed-up in cocaine addiction) and to all you piperazine fanatics! -Dick