title: Synthesis and in vitro evaluation of water-soluble 1,4-diphenethylpiperazine analogs as novel inhibitors of the vesicular monoamine transporter-2.
abstract: 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.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: Justin R
authors.initials: JR
authors.lastname: Nickell
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: John P
authors.initials: JP
authors.lastname: Culver
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
authors.forename: Venumadhav
authors.initials: V
authors.lastname: Janganati
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
authors.forename: Guangrong
authors.initials: G
authors.lastname: Zheng
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: Linda P
authors.initials: LP
authors.lastname: Dwoskin
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA. Electronic address: pacrooks@uams.edu.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Crooks
mesh_terms: D066298:In Vitro Techniques; D010879:Piperazines / Q000138:chemical synthesis* / Q000494:pharmacology*; D050493:Vesicular Monoamine Transport Proteins / Q000037:antagonists & inhibitors*
chemical_list: D010879:Piperazines; D050493:Vesicular Monoamine Transport Proteins
keywords: Dopamine uptake; Lobelane; Phenethyl bromides; Piperazine analogs; VMAT2