Synthesis and in vitro evaluation of water-soluble 1,4-diphenethylpiperazine analogs as novel inhibitors of the vesicular monoamine transporter-2

A small library of 1,4-diphenethylpiperazine analogs was synthesized and evaluated for inhibition of [³H]dihydrotetrabenazine binding and [³H]dopamine uptake at the vesicular monoamine transporter-2 (VMAT2). Results from these studies identified three novel molecules, 6b, 6e and 9a (K_i = 35 nM, 48 nM and 37 nM, respectively) that exhibit similar potency for inhibition of VMAT2 function compared with lobelane (K_i = 45 nM), 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.