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)
| Autor: | Kenner C. Rice, F.H.E. Wojnicki, Glowa, L. Radesca, Christina M. Dersch, Agu Pert, Richard B. Rothman, Dorota Matecka, John S. Partilla, de Costa Br |
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| Rok vydání: | 1996 |
| Předmět: |
Serotonin
Magnetic Resonance Spectroscopy Stereochemistry Substance-Related Disorders Dopamine Receptors Drug Sigma receptor Molecular Conformation Nerve Tissue Proteins Chemical synthesis Mass Spectrometry Piperazines chemistry.chemical_compound Cocaine Dopamine Uptake Inhibitors Drug Discovery medicine Animals Dopamine Plasma Membrane Transport Proteins Membrane Glycoproteins Molecular Structure Membrane Transport Proteins GBR-12935 Rats Piperazine chemistry Drug Design Catecholamine Molecular Medicine Enantiomer Reuptake inhibitor Carrier Proteins medicine.drug |
| Zdroj: | Journal of medicinal chemistry. 39(24) |
| ISSN: | 0022-2623 |
| Popis: | 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 sigma 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. |
| Databáze: | OpenAIRE |
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