Characterization of structurally diverse inhibitors at the monoamine transporters
School of Pharmacy
Christopher K Surratt
Jeffry D Madura
Wilson S Meng
Dopamine transporter, Molecular modeling, Monoamine transporter, Photoaffinity ligand, Pyrovalerone analogs, Serotonin transporter
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.
Huang, Y. (2010). Characterization of structurally diverse inhibitors at the monoamine transporters (Master's thesis, Duquesne University). Retrieved from https://dsc.duq.edu/etd/1503