Synthesis, molecular modeling, and biological studies of novel piperidine-based analogues of cocaine: Evidence of unfavorable interactions proximal to the 3α-position of the piperidine ring

Pavel A. Petukhov, Jianrong Zhang, Cheng Z. Wang, Yan Ping Ye, Kenneth M. Johnson, Alan P. Kozikowski

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

A qualitative model for the binding pocket proximal to the 3α-substituent of the piperidine-based monoamine transporter ligands was proposed and tested. Based on this model, a new series of druglike 3α-modified piperidine-based analogues of cocaine were designed, synthesized, and studied for their ability to inhibit reuptake of DA, 5-HT, and NE by the DA, 5-HT, and NE transporters. We found that the insertion of at least one additional methylene group between the piperidine ring and the polar group in the 3α-substituent dramatically improves the activity of the compounds that are generally inactive without this additional linker. Molecular modeling analysis showed that the more flexible 3α-substituents can avoid unfavorable interactions with the binding sites of DAT, SERT, and NET. The present results may have important implications for the elucidation of the structural differences between DA, 5-HT, and NE transporters and for the further design of new leads for development of cocaine abuse medication as well as certain neurological disorders such as ADHD and depression.

Original languageEnglish (US)
Pages (from-to)3009-3018
Number of pages10
JournalJournal of Medicinal Chemistry
Volume47
Issue number12
DOIs
StatePublished - Jun 3 2004

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Molecular modeling
Cocaine
Serotonin
Cocaine-Related Disorders
Aptitude
Nervous System Diseases
Binding Sites
Depression
Ligands
piperidine

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Synthesis, molecular modeling, and biological studies of novel piperidine-based analogues of cocaine : Evidence of unfavorable interactions proximal to the 3α-position of the piperidine ring. / Petukhov, Pavel A.; Zhang, Jianrong; Wang, Cheng Z.; Ye, Yan Ping; Johnson, Kenneth M.; Kozikowski, Alan P.

In: Journal of Medicinal Chemistry, Vol. 47, No. 12, 03.06.2004, p. 3009-3018.

Research output: Contribution to journalArticle

Petukhov, Pavel A. ; Zhang, Jianrong ; Wang, Cheng Z. ; Ye, Yan Ping ; Johnson, Kenneth M. ; Kozikowski, Alan P. / Synthesis, molecular modeling, and biological studies of novel piperidine-based analogues of cocaine : Evidence of unfavorable interactions proximal to the 3α-position of the piperidine ring. In: Journal of Medicinal Chemistry. 2004 ; Vol. 47, No. 12. pp. 3009-3018.
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