Synthesis and transporter binding properties of bridged piperazine analogues of 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine (GBR 12909).
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 (3)H-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 (IC(50) = 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 (IC(50) = 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 IC(50) 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 (IC(50) = 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.
Zhang
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Laboratory of Medicinal Chemistry, Building 8, Room B1-22, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-0815, USA.
Rothman
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Dersch
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de Costa
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Jacobson
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Rice
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D000818:Animals; D001921:Brain / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D002352:Carrier Proteins / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D006572:Heterocyclic Compounds, Bridged-Ring / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D066298:In Vitro Techniques; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000378:metabolism; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D012701:Serotonin / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins; D013329:Structure-Activity Relationship; D013574:Synaptosomes / Q000378:metabolism
C418117:3-(2-(bis(4-fluorophenyl)methoxy)ethyl)-8-(1H-indol-2-ylmethyl)-3,8-diazabicyclo(3.2.1)octane; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002352:Carrier Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D006572:Heterocyclic Compounds, Bridged-Ring; D007211:Indoles; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D010879:Piperazines; D050486:Serotonin Plasma Membrane Transport Proteins; C493216:Slc6a3 protein, rat; C493232:Slc6a4 protein, rat; D012701:Serotonin; C043425:vanoxerine; D004298:Dopamine