Interaction of tyrosine 151 in norepinephrine transporter with the 2β group of cocaine analog RTI-113

NEUROPHARMACOLOGY

卷:61

Article

Hill, Erik R.^1,2  Huang, Xiaoqin⁴  Zhan, Chang-Guo⁴  Carroll, F. Ivy⁵  Gu, Howard H.^1,2,3 

[1] Ohio State Univ, Coll Med, Dept Pharmacol, Columbus, OH 43210 USA

[2] Ohio State Univ, Coll Med, Ohio State Biochem Program, Columbus, OH 43210 USA

[3] Ohio State Univ, Coll Med, Dept Psychiat, Columbus, OH 43210 USA

[4] Univ Kentucky, Coll Pharm, Dept Pharmaceut Sci, Lexington, KY 40536 USA

[5] Res Triangle Inst, Ctr Organ & Med Chem, Res Triangle Pk, NC 27709 USA

关键词: Dopamine;    Norepinephrine;    Transporter;    Structure;    Cocaine;    Analog;    Binding site;    Computer modeling;   

DOI  :  10.1016/j.neuropharm.2011.03.014

来源: Elsevier

【 摘 要 】

Cocaine binds and inhibits dopamine transporter (DAT), norepinephrine transporter (NET) and serotonin transporter. The residues forming cocaine binding sites are unknown. RTI-113, a cocaine analog, is 100x more potent at inhibiting DAT than inhibiting NET. Here we show that removing the hydroxyl group from residue Tyr151 in NET by replacing it with Phe, the corresponding residue in DAT, increased the sensitivity of NET to RTI-113, while the reverse mutation in DAT decreased the sensitivity of DAT to RTI-113. In contrast, RTI-31, another cocaine analog having the same structure as RTI-113 but with the phenyl group at the 2 beta position replaced by a methyl group, inhibits the transporter mutants equally well whether a hydroxyl group is present at the residue or not. The data suggest that this residue contributes to cocaine binding site and is close to the 2 beta position of cocaine analogs. These results are consistent with our previously proposed cocaine-DAT binding model where cocaine initially binds to a site that does not overlap with, but is close to, the dopamine-binding site. Computational modeling and molecular docking yielded a binding model that explains the observed changes in RTI-113 inhibition potencies. (C) 2011 Elsevier Ltd. All rights reserved.

【 授权许可】

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