Characterization of structurally diverse inhibitors at the monoamine transporters

Yurong Huang

Defense Date

7-9-2010

Graduation Date

Summer 1-1-2010

Availability

Immediate Access

Submission Type

thesis

Degree Name

MS

Department

Pharmacology

School

School of Pharmacy

Committee Chair

Christopher K Surratt

Committee Member

Jeffry D Madura

Committee Member

Wilson S Meng

Keywords

Dopamine transporter, Molecular modeling, Monoamine transporter, Photoaffinity ligand, Pyrovalerone analogs, Serotonin transporter

Abstract

The SERT represents a major target for antidepressants such as S-citalopram. The SERT structure-function study is hindered due to lack of its high-resolution structure. The conventional SERT mutagenesis and pharmacology has been unconventionally guided by the LeuT-based comparative SERT model. The key SERT residues for S-citalopram binding were identified and further characterized via the binding and uptake assays. The results suggest the homology SERT model as a useful tool for better understanding the SERT structure-function relationship.

The DAT represents a principal biological target for abused psychostimulants. DAT structure-function studies have centered on the tropane-based blockers cocaine and benztropine, while the non-tropane blockers such as pyrovalerone have received less attention. To investigate the direct contacts between the DAT and non-tropane ligands, pyrovalerone analogs have been synthesized as potential irreversible photoaffinity ligands. The results demonstrate a multidisciplinary approach towards mapping the DAT residues involved in binding of non-tropane DAT ligands.

Format

PDF

Language

English

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