Molecular modeling, structure-activity relationships and functional antagonism studies of 4-hydroxy-1-methyl-4-(4-methylphenyl)-3-piperidyl 4-methylphenyl ketones as a novel class of dopamine transporter inhibitors

Shaomeng Wang, Sukumar Sakamuri, Istvan J. Enyedy, Alan P. Kozikowski, Wahiduz A. Zaman, Kenneth M. Johnson

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

We previously disclosed the discovery of 4-hydroxy-1-methyl-4-(4-methylphenyl)-3-piperidyl 4-methylphenyl ketone (3) as a novel class of dopamine transporter (DAT) inhibitors and showed that (±)-3 has a significant functional antagonism against cocaine in vitro. Our previous preliminary structure-activity relationship study led to identification of a more potent DAT inhibitor [(±)-4] but this compound failed to show any significant functional antagonism. To search for more potent analogues than 3 but still displaying significant functional antagonism, further SARs, molecular modeling studies and in vitro pharmacological evaluation of this novel class of DAT inhibitors were performed. Sixteen new analogues were synthesized in racemic form and evaluated as DAT inhibitors. It was found that seven new analogues are reasonably potent DAT inhibitors with Ki values of 0.041-0.30 and 0.052-0.16μM in [3H]mazindol binding and inhibition of DA reuptake. Chiral isomers of several potent DAT inhibitors were obtained through chiral HPLC separation and evaluated as inhibitors at all the three monoamine transporter sites. In general, the (-)- isomer is more active than the (+)-isomer in inhibition of DA reuptake and all the (-)-isomers are selective inhibitors at the DAT site. Evaluation of cocaine's effect on dopamine uptake in the presence and absence of (+)-3 and (-)-3 showed that (-)-3 is responsible for the functional antagonism obtained with the origin lead (±)-3 in binding and inhibition of DA reuptake, appeared to have improved functional antagonism as compared to (±)-3.

Original languageEnglish
Pages (from-to)1753-1764
Number of pages12
JournalBioorganic and Medicinal Chemistry
Volume9
Issue number7
DOIs
StatePublished - 2001

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Dopamine Plasma Membrane Transport Proteins
Molecular modeling
Structure-Activity Relationship
Molecular Structure
Isomers
Cocaine
Mazindol
4-hydroxy-1-methyl-4-(4-methylphenyl)-3-piperidyl 4-methylphenyl ketone
Dopamine
High Pressure Liquid Chromatography
Pharmacology

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Organic Chemistry
  • Drug Discovery
  • Pharmaceutical Science

Cite this

Molecular modeling, structure-activity relationships and functional antagonism studies of 4-hydroxy-1-methyl-4-(4-methylphenyl)-3-piperidyl 4-methylphenyl ketones as a novel class of dopamine transporter inhibitors. / Wang, Shaomeng; Sakamuri, Sukumar; Enyedy, Istvan J.; Kozikowski, Alan P.; Zaman, Wahiduz A.; Johnson, Kenneth M.

In: Bioorganic and Medicinal Chemistry, Vol. 9, No. 7, 2001, p. 1753-1764.

Research output: Contribution to journalArticle

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