Further SAR studies of piperidine-based analogues of cocaine. 2. Potent dopamine and serotonin reuptake inhibitors

Amir P. Tamiz, Jianrong Zhang, Judith L. Flippen-Anderson, Mei Zhang, Kenneth M. Johnson, Olivier Deschaux, Srihari Tella, Alan P. Kozikowski

Research output: Contribution to journalArticle

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Abstract

The synthesis and monoamine transporter activity of additional members of a series of 3,4-disubstituted piperidines (truncated analogues of the WIN series) are described. All members of this series were prepared from arecoline hydrobromide in optically pure form and were evaluated for their ability to inhibit high affinity uptake of dopamine (DA), serotonin (5-HT) and norepinephrine (NE) into rat brain nerve endings (synaptosomes). Most of the compounds prepared in this series are reasonably potent DAT inhibitors (K(i) values of 4-400 nM) and have selectivity for the 5-HT transporter relative to both the NE transporter (3-9-fold) and to the DAT (Å25-fold). In the present series, (-)-methyl 1-methyl-4β-(2-naphthyl)piperidine-3β- carboxylate (6) was found to be the most potent piperidine-based ligand, exhibiting K(i)'s of 21 nM and 7.6 nM at the DAT and 5-HTT, respectively. While the 5-HTT activity of compound 6 is comparable to that of the antidepressant medication fluoxetine, it is less selective. As is apparent from the data presented, the naphthyl substituted piperidines 6-9, which differ in their stereochemistry, show different degrees of selectivity for the three transporters. Consistent with results reported in the literature for the tropane analogues, removal of the methyl group from the nitrogen atom of 9 leads to a further enhancement in 5-HTT activity. To examine the in vivo effects of these piperidines, preliminary behavioral screening was carried out on piperidine 14. Despite its 2.5-fold greater DAT activity compared to cocaine, piperidine 14 was found to be about 2.5-fold less potent in increasing distance traveled in mice. However, consistent with its DAT activity, piperidine 14 was found to be about 2.5-fold more potent than cocaine in enhancing stereotypic movements. Further studies of these piperidine-based ligands may provide valuable insights into the pharmacological mechanisms underlying the enhancement in distance traveled versus stereotypic movements. The present results have important implications for better understanding the structural motifs required in the design of agents with specific potency and selectivity at monoamine transporters.

Original languageEnglish
Pages (from-to)1215-1222
Number of pages8
JournalJournal of Medicinal Chemistry
Volume43
Issue number6
DOIs
StatePublished - Mar 23 2000

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Dopamine Uptake Inhibitors
Serotonin Uptake Inhibitors
Cocaine
Piperidines
Serotonin
Arecoline
Tropanes
Norepinephrine Plasma Membrane Transport Proteins
Ligands
Stereochemistry
Nerve Endings
Synaptosomes
Fluoxetine
Antidepressive Agents
piperidine
Rats
Dopamine
Brain
Norepinephrine
Screening

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Tamiz, A. P., Zhang, J., Flippen-Anderson, J. L., Zhang, M., Johnson, K. M., Deschaux, O., ... Kozikowski, A. P. (2000). Further SAR studies of piperidine-based analogues of cocaine. 2. Potent dopamine and serotonin reuptake inhibitors. Journal of Medicinal Chemistry, 43(6), 1215-1222. https://doi.org/10.1021/jm9905561

Further SAR studies of piperidine-based analogues of cocaine. 2. Potent dopamine and serotonin reuptake inhibitors. / Tamiz, Amir P.; Zhang, Jianrong; Flippen-Anderson, Judith L.; Zhang, Mei; Johnson, Kenneth M.; Deschaux, Olivier; Tella, Srihari; Kozikowski, Alan P.

In: Journal of Medicinal Chemistry, Vol. 43, No. 6, 23.03.2000, p. 1215-1222.

Research output: Contribution to journalArticle

Tamiz, AP, Zhang, J, Flippen-Anderson, JL, Zhang, M, Johnson, KM, Deschaux, O, Tella, S & Kozikowski, AP 2000, 'Further SAR studies of piperidine-based analogues of cocaine. 2. Potent dopamine and serotonin reuptake inhibitors', Journal of Medicinal Chemistry, vol. 43, no. 6, pp. 1215-1222. https://doi.org/10.1021/jm9905561
Tamiz, Amir P. ; Zhang, Jianrong ; Flippen-Anderson, Judith L. ; Zhang, Mei ; Johnson, Kenneth M. ; Deschaux, Olivier ; Tella, Srihari ; Kozikowski, Alan P. / Further SAR studies of piperidine-based analogues of cocaine. 2. Potent dopamine and serotonin reuptake inhibitors. In: Journal of Medicinal Chemistry. 2000 ; Vol. 43, No. 6. pp. 1215-1222.
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