Discovery of a novel dopamine transporter inhibitor, 4-hydroxy-1-methyl- 4-(4-methylphenyl)-3-piperidyl 4-methylphenyl ketone, as a potential cocaine antagonist through 3D-database pharmacophore searching. Molecular modeling, structure - Activity relationships, and behavioral pharmacological studies

Shaomeng Wang, Sukumar Sakamuri, Istvan J. Enyedy, Alan P. Kozikowski, Olivier Deschaux, Bidhan C. Bandyopadhyay, Srihari R. Tella, Wahiduz A. Zaman, Kenneth M. Johnson

Research output: Contribution to journalArticle

Abstract

A novel, fairly potent dopamine transporter (DAT) inhibitor, 4-hydroxy- 1-methyl-4-(4-methylphenyl)-3-piperidyl 4-methylphenyl ketone (3, K(i) values of 492 and 360 nM in binding affinity and inhibition of dopamine reuptake, respectively), with significant functional antagonism against cocaine and a different in vitro pharmacological profile from cocaine at the three transporter sites (dopamine, serotonin, and norepinephrine) was discovered through 3D-database pharmacophore searching. Through structure-activity relationships and molecular modeling studies, we found that hydrophobicity and conformational preference are two additional important parameters that determine affinity at the DAT site. Chemical modifications of the lead compound (3) led to a high affinity analogue (6, K(i) values of 11 and 55 nM in binding affinity and inhibition of dopamine reuptake, respectively). In behavioral pharmacological testing, 6 mimics partially the effect of cocaine in increasing locomotor activity in mice but lacks cocaine-like discriminative stimulus effect in rats. Taken together, these data suggest that 6 represents a promising lead for further evaluations as potential therapy for the treatment of cocaine abuse.

Original languageEnglish (US)
Pages (from-to)351-360
Number of pages10
JournalJournal of Medicinal Chemistry
Volume43
Issue number3
DOIs
StatePublished - Feb 10 2000
Externally publishedYes

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Dopamine Plasma Membrane Transport Proteins
Molecular modeling
Structure-Activity Relationship
Molecular Structure
Cocaine
Databases
Pharmacology
Dopamine
Cocaine-Related Disorders
Lead compounds
Locomotion
Hydrophobic and Hydrophilic Interactions
Chemical modification
Serotonin
Hydrophobicity
Norepinephrine
Rats
4-hydroxy-1-methyl-4-(4-methylphenyl)-3-piperidyl 4-methylphenyl ketone
Testing
Lead

ASJC Scopus subject areas

  • Organic Chemistry

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Discovery of a novel dopamine transporter inhibitor, 4-hydroxy-1-methyl- 4-(4-methylphenyl)-3-piperidyl 4-methylphenyl ketone, as a potential cocaine antagonist through 3D-database pharmacophore searching. Molecular modeling, structure - Activity relationships, and behavioral pharmacological studies. / Wang, Shaomeng; Sakamuri, Sukumar; Enyedy, Istvan J.; Kozikowski, Alan P.; Deschaux, Olivier; Bandyopadhyay, Bidhan C.; Tella, Srihari R.; Zaman, Wahiduz A.; Johnson, Kenneth M.

In: Journal of Medicinal Chemistry, Vol. 43, No. 3, 10.02.2000, p. 351-360.

Research output: Contribution to journalArticle

Wang, Shaomeng ; Sakamuri, Sukumar ; Enyedy, Istvan J. ; Kozikowski, Alan P. ; Deschaux, Olivier ; Bandyopadhyay, Bidhan C. ; Tella, Srihari R. ; Zaman, Wahiduz A. ; Johnson, Kenneth M. / Discovery of a novel dopamine transporter inhibitor, 4-hydroxy-1-methyl- 4-(4-methylphenyl)-3-piperidyl 4-methylphenyl ketone, as a potential cocaine antagonist through 3D-database pharmacophore searching. Molecular modeling, structure - Activity relationships, and behavioral pharmacological studies. In: Journal of Medicinal Chemistry. 2000 ; Vol. 43, No. 3. pp. 351-360.
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