Synthesis and Transporter Binding Properties of Bridged Piperazine Analogues of 1-{2-[Bis(4-fluorophenyl)methoxy]ethyl}-4-(3-phenylpropyl)piperazine (GBR 12909)

• Published in: Journal of medicinal chemistry Vol. 43; no. 25; pp. 4840 - 4849
• Main Authors: Zhang, Ying, Rothman, Richard B, Dersch, Christina M, de Costa, Brian R, Jacobson, Arthur E, Rice, Kenner C
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 14.12.2000; Amer Chemical Soc
• Subjects: Biological and medical sciences; Catecholaminergic system; Chemistry, Medicinal; Life Sciences & Biomedicine; Medical sciences; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Science & Technology; NONHUMAN-PRIMATES; EXTRACELLULAR DOPAMINE; RAT; 1-<2-<BIS(4-FLUOROPHENYL)METHOXY>ETHYL>-4-(3-PHENYLPROPYL)PIPERAZINES GBR-12935; DOPAMINE REUPTAKE INHIBITORS; NOREPINEPHRINE TRANSPORTER; ANIMAL-MODELS; COCAINE-ABUSE; KNOCKOUT MICE; AMPHETAMINE; Dopamine; Rat; Nitrogen heterocycle; Rodentia; Central nervous system; Benzene derivatives; Aminoether; Selectivity; Reuptake inhibitor; In vitro; Vertebrata; Biological fixation; Mammalia; Structure activity relation; Membrane transport; Animal; Bicyclic compound; Neurotransmitter; Affinity; Fluorine Organic compounds; Indole derivatives; Chemical synthesis; Carrier protein; Brain (vertebrata)
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm000300r

A series of analogues related to 1-[2-(diphenylmethoxy)ethyl]-4-(3-phenylpropyl)piperazine (2) and 1-{2-[bis(4-fluorophenyl)methoxy]ethyl}-4-(3-phenylpropyl)piperazine (3) (GBR 12935 and GBR 12909, respectively), in which the piperazine moiety was replaced by bridged piperazines for structural rigidity, has been designed, synthesized, and evaluated for their ability to bind to the dopamine transporter (DAT) and to inhibit the uptake of 3H-labeled dopamine (DA). The binding data indicated that compounds 7 and 11, the N-methyl- and N-propylphenyl-3,8-diaza[3.2.1]bicyclooctane analogues of 3, showed high affinity for the DAT (IC50 = 8.0 and 8.2 nM, respectively), and 7 had high selectivity at the DAT relative to the serotonin transporter (SERT) (88- and 93-fold for binding and reuptake, respectively). They also displayed linear activity in DA uptake inhibition, possessing a similar binding and reuptake inhibition profile to 3. The N-indolylmethyl analogue 16 showed the highest affinity (IC50 = 1.4 nM) of the series, with a 6-fold increase over its corresponding N-phenypropyl derivative 11. Interestingly, this compound exhibited a high ratio (29-fold) of IC50 for the inhibition of DA reuptake versus binding to the DAT. Replacing the piperazine moiety of 2 and 3 with (1S,4S)-2,5-diazabicyclo[2.2.1]heptane resulted in compounds 23−26, which showed moderate to poor affinity (IC50 = 127−1170 nM) for the DAT. Substitution of the homopiperazine moiety of 4 with a more rigid 3,9-diazabicyclo[4.2.1]nonane gave compounds 28−33. However, the binding data showed that compound 32 displayed a 10-fold decrease in affinity at the DAT and a 100-fold decrease in selectivity at the DAT relative to the SERT compared to its corresponding homopiperazine compound 4.