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Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Synthesis and in vitro evaluation of water-soluble 1,4-diphenethylpiperazine analogs as novel inhibitors of the vesicular monoamine transporter-2.
Bioorganic & Medicinal Chemistry Letters 2016 September 16
A small library of 1,4-diphenethylpiperazine analogs was synthesized and evaluated for inhibition of [(3)H]dihydrotetrabenazine binding and [(3)H]dopamine uptake at the vesicular monoamine transporter-2 (VMAT2). Results from these studies identified three novel molecules, 6b, 6e and 9a (Ki=35nM, 48nM and 37nM, respectively) that exhibit similar potency for inhibition of VMAT2 function compared with lobelane (Ki=45nM), and importantly, have enhanced water-solubility when compared to the previously reported 1,4-diphenethylpiperidine analogs. These 1,4-diphenethylpiperazine analogs constitute promising new leads in the discovery of potential pharmacotherapeutics for treatment of methamphetamine use disorders.
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