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)

• Published in: Journal of medicinal chemistry Vol. 39; no. 24; pp. 4704 - 4716
• Main Authors: Matecka, Dorota, Rothman, Richard B, Radesca, Lilian, de Costa, Brian R, Dersch, Christina M, Partilla, John S, Pert, Agu, Glowa, John R, Wojnicki, Francis H. E, Rice, Kenner C
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 22.11.1996; Amer Chemical Soc
• Subjects: Animals; Biological and medical sciences; Carrier Proteins - drug effects; Carrier Proteins - metabolism; Chemistry, Medicinal; Cocaine - pharmacology; Dopamine - metabolism; Dopamine Plasma Membrane Transport Proteins; Dopamine Uptake Inhibitors - chemical synthesis; Dopamine Uptake Inhibitors - pharmacology; Drug addictions; Drug Design; Life Sciences & Biomedicine; Magnetic Resonance Spectroscopy; Mass Spectrometry; Medical sciences; Membrane Glycoproteins; Membrane Transport Proteins; Molecular Conformation; Molecular Structure; Nerve Tissue Proteins; Pharmacology & Pharmacy; Piperazines - chemical synthesis; Piperazines - metabolism; Piperazines - pharmacology; Rats; Receptors, Drug - metabolism; Science & Technology; Serotonin - metabolism; Substance-Related Disorders - therapy; Toxicology; BIOGENIC-AMINE TRANSPORTERS; GBR-12909; SIGMA-RECEPTORS; COCAINE ANTAGONISTS; RHESUS-MONKEYS; ANALOGS; AFFINITY; PHARMACOLOGY; RAT CAUDATE MEMBRANES; BINDING-SITES; Five membered ring; Dopamine; Nitrogen heterocycle; Sigma receptor; Steric hindrance; Catecholamine; Reuptake inhibitor; In vitro; Prevention; Diamine; Biological fixation; Treatment; Structure activity relation; Membrane transport; Enantiomer; Neurotransmitter; Cocaine; Drug of abuse; Chemical synthesis; Seven membered ring
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm960305h

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 σ 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.