Lobelane analogues containing 4-hydroxy and 4-(2-fluoroethoxy) aromatic substituents: Potent and selective inhibitors of [3H]dopamine uptake at the vesicular monoamine transporter-2

Abstract

A series of lobelane and GZ-793A analogues that incorporate aromatic 4-hydroxy and 4-(2-fluoroethoxy) substituents were synthesized and evaluated for inhibition of [3H]dopamine (DA) uptake at the vesicular monoamine transporter-2 (VMAT2) and the dopamine transporter (DAT), and [3H]serotonin uptake at the serotonin transporter (SERT). Most of these compounds exhibited potent inhibition of DA uptake at VMAT2 in the nanomolar range (Ki = 30–70 nM). The two most potent analogues, 7 and 14, both exhibited a Ki value of 31 nM for inhibition of VMAT2. The lobelane analogue 14, incorporating 4-(2-fluoroethoxy) and 4-hydroxy aromatic substituents, exhibited 96- and 335-fold greater selectivity for VMAT2 versus DAT and SERT, respectively, in comparison to lobelane. Thus, lobelane analogues bearing hydroxyl and fluoroethoxy moieties retain the high affinity for VMAT2 of the parent compound, while enhancing selectivity for VMAT2 versus the plasmalemma transporters.

Fluoroethoxy-1,4-diphenethylpiperidine and piperazine derivatives: Potent and selective inhibitors of [ 3 H]dopamine uptake at the vesicular monoamine transporter-2

“…8,20 The majority of the analogs exhibited K i values in the nanomolar range (K i = 0.014–0.073 µM) for inhibition of VMAT2 function. Compound 15d , 1-(2-chlorophenethyl)-4-(2-fluoroethoxyphenethyl)piperazine, was the most potent inhibitor of [ 3 H]DA uptake at VMAT2, exhibiting a K i value of 0.014 µM and exhibiting 3-fold greater affinity for VMAT2 compared to lobelane (K i = 0.045 µM).…”

“…In the SERT assay, 20 K i values were in the range of 0.070 µM to 6 μM (Table 1). Thus, for the majority of the compounds in this series, good selectivity for VMAT2 over SERT also was found.…”