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

A. P. Tamiz, B. C. Bandyopadhyay, J. Zhang, J. L. Flippen-Anderson, M. Zhang, C. Z. Wang, K. M. Johnson, S. Tella, A. P. Kozikowski

Research output: Contribution to journalArticle

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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 (Ki = 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 described herein constitute a new class of monoamine reuptake inhibitors that exhibit varying levels of monoamine transporter activity and selectivity, and these ligands may serve as lead candidates in the discovery of new therapeutics to treat a range of neurological disorders including cocaine addiction.

Original languageEnglish (US)
Pages (from-to)1615-1622
Number of pages8
JournalJournal of Medicinal Chemistry
Volume44
Issue number10
DOIs
StatePublished - May 10 2001

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Pharmacology
Ligands
Cocaine
Serotonin
Locomotion
Rats
Monomers
Cocaine-Related Disorders
Dopamine Plasma Membrane Transport Proteins
Aptitude
Nerve Endings
Synaptosomes
piperidine
Nervous System Diseases
Dopamine
Brain
Norepinephrine
Pharmaceutical Preparations
Therapeutics

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Tamiz, A. P., Bandyopadhyay, B. C., Zhang, J., Flippen-Anderson, J. L., Zhang, M., Wang, C. Z., ... Kozikowski, A. P. (2001). Pharmacological and behavioral analysis of the effects of some bivalent ligand-based monoamine reuptake inhibitors. Journal of Medicinal Chemistry, 44(10), 1615-1622. https://doi.org/10.1021/jm000552s

Pharmacological and behavioral analysis of the effects of some bivalent ligand-based monoamine reuptake inhibitors. / Tamiz, A. P.; Bandyopadhyay, B. C.; Zhang, J.; Flippen-Anderson, J. L.; Zhang, M.; Wang, C. Z.; Johnson, K. M.; Tella, S.; Kozikowski, A. P.

In: Journal of Medicinal Chemistry, Vol. 44, No. 10, 10.05.2001, p. 1615-1622.

Research output: Contribution to journalArticle

Tamiz, AP, Bandyopadhyay, BC, Zhang, J, Flippen-Anderson, JL, Zhang, M, Wang, CZ, Johnson, KM, Tella, S & Kozikowski, AP 2001, 'Pharmacological and behavioral analysis of the effects of some bivalent ligand-based monoamine reuptake inhibitors', Journal of Medicinal Chemistry, vol. 44, no. 10, pp. 1615-1622. https://doi.org/10.1021/jm000552s
Tamiz, A. P. ; Bandyopadhyay, B. C. ; Zhang, J. ; Flippen-Anderson, J. L. ; Zhang, M. ; Wang, C. Z. ; Johnson, K. M. ; Tella, S. ; Kozikowski, A. P. / Pharmacological and behavioral analysis of the effects of some bivalent ligand-based monoamine reuptake inhibitors. In: Journal of Medicinal Chemistry. 2001 ; Vol. 44, No. 10. pp. 1615-1622.
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