PMID: 11334571May 4, 2001Paper

Pharmacological and behavioral analysis of the effects of some bivalent ligand-based monoamine reuptake inhibitors

Journal of Medicinal Chemistry
A P TamizA P Kozikowski

Abstract

Novel piperidine-based bivalent ligands were prepared in enantiomerically pure form and evaluated for their ability to inhibit reuptake of dopamine (DA), serotonin (5-HT), and norepinephrine (NE) into rat brain nerve endings (synaptosomes). In this study, we have succeeded in using (1) the length of the linking chain connecting the two piperidine-based monomer units and (2) the absolute configuration of the piperidine monomer as a means to tailor activity and selectivity at the three monoamine transporters tested. In this series, the bivalent ligand 16, comprised of two (+)-trans-piperidine units linked by a pentamethylene spacer, exhibits a combination of high DA transporter (DAT) and 5-HT transporter (SERT) activity (K(i) = 39 nM and 7 nM, respectively). Piperidine 16 is capable of reducing cocaine's locomotor effects in mice while not having any effect on locomotion when tested alone. Additionally, compound 16 (1-10 mg/kg) does not substitute for cocaine in drug discrimination studies in rats. However, the analogous bivalent ligand 15 comprised of two (-)-trans-piperidine units, which is SERT selective, was less effective in antagonizing cocaine's locomotor stimulant activity. The piperidine-based bivalent inhibitors describ...Continue Reading

References

Aug 15, 1992·Proceedings of the National Academy of Sciences of the United States of America·S KitayamaG R Uhl
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Citations

Jun 12, 2003·Bioorganic & Medicinal Chemistry Letters·Keith FandrickJohn R Cashman
Mar 5, 2003·Bioorganic & Medicinal Chemistry·Sukumar SakamuriShaomeng Wang
Sep 18, 2010·Journal of Medicinal Chemistry·Yanan ZhangBrian F Thomas
Feb 18, 2021·Journal of Natural Products·Darius P ZlotosUlrike Holzgrabe
Dec 6, 2017·Organic Letters·Nicolai Stuhr-HansenOla Blixt
Jul 12, 2002·Journal of Medicinal Chemistry·Pavel A PetukhovSrihari R Tella
Sep 6, 2002·Journal of Medicinal Chemistry·William J HoulihanTheresa A Kopajtic

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