Heteroaromatic analogs of 1-[2-(diphenylmethoxy)ethyl]- and 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazines (GBR 12935 and GBR 12909) as high-affinity dopamine reuptake inhibitors
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Matecka, D
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机构:NIDDKD, MED CHEM LAB, NIH, BETHESDA, MD 20892 USA
Matecka, D
Lewis, D
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机构:NIDDKD, MED CHEM LAB, NIH, BETHESDA, MD 20892 USA
Lewis, D
Rothman, RB
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机构:NIDDKD, MED CHEM LAB, NIH, BETHESDA, MD 20892 USA
Rothman, RB
Dersch, CM
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机构:NIDDKD, MED CHEM LAB, NIH, BETHESDA, MD 20892 USA
Dersch, CM
Wojnicki, FHE
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机构:NIDDKD, MED CHEM LAB, NIH, BETHESDA, MD 20892 USA
Wojnicki, FHE
Glowa, JR
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机构:NIDDKD, MED CHEM LAB, NIH, BETHESDA, MD 20892 USA
Glowa, JR
DeVries, AC
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机构:NIDDKD, MED CHEM LAB, NIH, BETHESDA, MD 20892 USA
DeVries, AC
Pert, A
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机构:NIDDKD, MED CHEM LAB, NIH, BETHESDA, MD 20892 USA
Pert, A
Rice, KC
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机构:NIDDKD, MED CHEM LAB, NIH, BETHESDA, MD 20892 USA
Rice, KC
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[1] NIDDKD, MED CHEM LAB, NIH, BETHESDA, MD 20892 USA
[2] NIDA, ADDICT RES CTR,IRP,CLIN PSYCHOPHARMACOL SECT,NIH, BALTIMORE, MD 21224 USA
[3] NIMH, BIOL PSYCHIAT BRANCH, NIH, BETHESDA, MD 20892 USA
A new series of heteroaromatic GBR 12935 [1-[2-(diphenylmethoxy)ethyl]-4-(3-phenylpropyl)-piperazine] (1) and GBR 12909 [1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)-piperazine] (2) analogs was synthesized and evaluated as dopamine transporter (DAT) ligands. Analogs 5-16, in which the benzene ring in the phenylpropyl side chain of the GBR molecule had been replaced with a thiophene, furan, or pyridine ring, exhibited high affinity and selectivity for the DAT vs serotonin transporter (SERT) and stimulated locomotor activity in rats in a manner similar to the parent compound 2. In cocaine and food self-administration studies in rhesus monkeys, both thiophene-containing (6 and 8) and pyridine-containing (14 and 16) derivatives displayed potency comparable to 2 in decreasing the cocaine-maintained responding at the doses tested (0.3, 1.7, and 3 mg/kg). However, these compounds did not produce the degree of separation between food- and cocaine-maintained responding that was seen with 2. Among the bicyclic fused-ring congeners 17-38, the indole-containing analog of 2, 22, showed the greatest affinity for binding to the DAT, with IC50 = 0.7 nM, whereas the corresponding indole-containing derivative of 1, 21, displayed the highest selectivity (over 600-fold) at this site vs the SEPT site.
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NIDDK, Lab Med Chem, NIH, Bethesda, MD USANIDDK, Lab Med Chem, NIH, Bethesda, MD USA
Glowa, John R.
Wojnicki, Francis H. E.
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NIDDK, Lab Med Chem, NIH, Bethesda, MD USANIDDK, Lab Med Chem, NIH, Bethesda, MD USA
Wojnicki, Francis H. E.
Matecka, Dorota
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NIDDK, Lab Med Chem, NIH, Bethesda, MD USANIDDK, Lab Med Chem, NIH, Bethesda, MD USA
Matecka, Dorota
Bacher, John D.
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NIH, Vet Resources Program, Natl Ctr Res Resources, Bethesda, MD 20892 USANIDDK, Lab Med Chem, NIH, Bethesda, MD USA
Bacher, John D.
Mansbach, Robert S.
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Med Coll Virginia, Dept Pharmacol & Toxicol, Richmond, VA USA
Pfizer Inc, Cent Res Div, Groton, CT 06340 USANIDDK, Lab Med Chem, NIH, Bethesda, MD USA
Mansbach, Robert S.
Balster, Robert L.
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Med Coll Virginia, Dept Pharmacol & Toxicol, Richmond, VA USANIDDK, Lab Med Chem, NIH, Bethesda, MD USA
Balster, Robert L.
Rice, Kenner C.
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NIDDK, Lab Med Chem, NIH, Bethesda, MD USANIDDK, Lab Med Chem, NIH, Bethesda, MD USA
机构:
NIDDK, Lab Med Chem, NIH, Bethesda, MD USANIDDK, Lab Med Chem, NIH, Bethesda, MD USA
Glowa, John R.
Wojnicki, Francis H. E.
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NIDDK, Lab Med Chem, NIH, Bethesda, MD USANIDDK, Lab Med Chem, NIH, Bethesda, MD USA
Wojnicki, Francis H. E.
Matecka, Dorota
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NIDDK, Lab Med Chem, NIH, Bethesda, MD USANIDDK, Lab Med Chem, NIH, Bethesda, MD USA
Matecka, Dorota
Bacher, John D.
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NIH, Vet Resources Program, Natl Ctr Res Resources, Bethesda, MD 20892 USANIDDK, Lab Med Chem, NIH, Bethesda, MD USA
Bacher, John D.
Mansbach, Robert S.
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机构:
Med Coll Virginia, Dept Pharmacol & Toxicol, Richmond, VA USA
Pfizer Inc, Cent Res Div, Groton, CT 06340 USANIDDK, Lab Med Chem, NIH, Bethesda, MD USA
Mansbach, Robert S.
Balster, Robert L.
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Med Coll Virginia, Dept Pharmacol & Toxicol, Richmond, VA USANIDDK, Lab Med Chem, NIH, Bethesda, MD USA
Balster, Robert L.
Rice, Kenner C.
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NIDDK, Lab Med Chem, NIH, Bethesda, MD USANIDDK, Lab Med Chem, NIH, Bethesda, MD USA