2,3-Disubstituted quinuclidines as a novel class of dopamine transporter inhibitors

Sukumar Sakamuri, Istvan J. Enyedy, Wahiduz A. Zaman, Srihari R. Tella, Alan P. Kozikowski, Judith L. Flippen-Anderson, Tivadar Farkas, Kenneth M. Johnson, Shaomeng Wang

Research output: Contribution to journalArticle

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Abstract

There is considerable interest in developing dopamine transporter (DAT) inhibitors as potential therapies for the treatment of cocaine abuse. We report herein our pharmacophore-based discovery and molecular modeling-assisted rational design of 2,3-disubstituted quinuclidines as potent DAT inhibitors with a novel chemical scaffold. Through 3-D-database pharmacophore searching, compound 12 was identified as a very weak DAT inhibitor with Ki values of 7.3 and 8.9 μM in [3H]mazindol binding and in inhibition of dopamine reuptake, respectively. Molecular modeling-assisted rational design and chemical modifications led to identification of potent analogues (-)-29 and 34 with Ki values of 14 and 32 nM for both compounds in binding affinity and inhibition of dopamine reuptake, respectively. Behavioral pharmacological evaluations in rodents showed that 34 has a profile very different from cocaine. While 34 is substantially more potent than cocaine as a DAT inhibitor, it is approximately four times less potent than cocaine in mimicking the discriminative stimulus properties of cocaine in rat. On the other hand, 34 (3-30 mg/kg) lacks either the locomotor stimulant or stereotypic properties of cocaine in mice. Importantly, 34 blocks locomotor stimulant activity induced by 20 mg/kg cocaine in mice, with an estimated ED50 of 19 mg/kg. Taken together, our data suggest that 34 represents a class of potent DAT inhibitors with a novel chemical scaffold and a behavioral pharmacological profile different from that of cocaine in rodents. Thus, 34 may serve as a novel lead compound in the ultimate development of therapeutic entities for cocaine abuse and/or addiction.

Original languageEnglish (US)
Pages (from-to)1123-1136
Number of pages14
JournalBioorganic and Medicinal Chemistry
Volume11
Issue number6
DOIs
StatePublished - Mar 2003

Fingerprint

Quinuclidines
Dopamine Plasma Membrane Transport Proteins
Cocaine
Cocaine-Related Disorders
Molecular modeling
Rodentia
Dopamine
Mazindol
Scaffolds
Pharmacology
Lead compounds
Locomotion
Chemical modification
Databases
Rats

ASJC Scopus subject areas

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

Cite this

Sakamuri, S., Enyedy, I. J., Zaman, W. A., Tella, S. R., Kozikowski, A. P., Flippen-Anderson, J. L., ... Wang, S. (2003). 2,3-Disubstituted quinuclidines as a novel class of dopamine transporter inhibitors. Bioorganic and Medicinal Chemistry, 11(6), 1123-1136. https://doi.org/10.1016/S0968-0896(02)00450-9

2,3-Disubstituted quinuclidines as a novel class of dopamine transporter inhibitors. / Sakamuri, Sukumar; Enyedy, Istvan J.; Zaman, Wahiduz A.; Tella, Srihari R.; Kozikowski, Alan P.; Flippen-Anderson, Judith L.; Farkas, Tivadar; Johnson, Kenneth M.; Wang, Shaomeng.

In: Bioorganic and Medicinal Chemistry, Vol. 11, No. 6, 03.2003, p. 1123-1136.

Research output: Contribution to journalArticle

Sakamuri, S, Enyedy, IJ, Zaman, WA, Tella, SR, Kozikowski, AP, Flippen-Anderson, JL, Farkas, T, Johnson, KM & Wang, S 2003, '2,3-Disubstituted quinuclidines as a novel class of dopamine transporter inhibitors', Bioorganic and Medicinal Chemistry, vol. 11, no. 6, pp. 1123-1136. https://doi.org/10.1016/S0968-0896(02)00450-9
Sakamuri S, Enyedy IJ, Zaman WA, Tella SR, Kozikowski AP, Flippen-Anderson JL et al. 2,3-Disubstituted quinuclidines as a novel class of dopamine transporter inhibitors. Bioorganic and Medicinal Chemistry. 2003 Mar;11(6):1123-1136. https://doi.org/10.1016/S0968-0896(02)00450-9
Sakamuri, Sukumar ; Enyedy, Istvan J. ; Zaman, Wahiduz A. ; Tella, Srihari R. ; Kozikowski, Alan P. ; Flippen-Anderson, Judith L. ; Farkas, Tivadar ; Johnson, Kenneth M. ; Wang, Shaomeng. / 2,3-Disubstituted quinuclidines as a novel class of dopamine transporter inhibitors. In: Bioorganic and Medicinal Chemistry. 2003 ; Vol. 11, No. 6. pp. 1123-1136.
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