Novel N-1,2-Dihydroxypropyl Analogs of Lobelane Inhibit Vesicular Monoamine Transporter-2 Function and Methamphetamine-Evoked Dopamine Release

Abstract

Lobelane, a chemically defunctionalized saturated analog of lobeline, has increased selectivity for the vesicular monoamine transporter 2 (VMAT2) compared with the parent compound. Lobelane inhibits methamphetamine-evoked dopamine (DA) release and decreases methamphetamine self-administration. Unfortunately, tolerance develops to the ability of lobelane to decrease these behavioral effects of methamphetamine. Lobelane has low water solubility, which is problematic for drug development. The aim of the current study was to determine the pharmacological effect of replacement of the N-methyl moiety with a chiral N-1,2-dihydroxypropyl (N-1,2-diol) moiety, which enhances water solubility, altering the configuration of the N-1,2-diol moiety and incorporating phenyl ring substituents into the analogs. To determine VMAT2 selectivity, structure-activity relationships also were generated for inhibition of DA and serotonin transporters. Analogs with the highest potency for inhibiting DA uptake at VMAT2 and at least 10-fold selectivity were evaluated further for ability to inhibit methamphetamine-evoked DA release from superfused striatal slices. (R)-3-[2,6-cis-di(4-methoxyphenethyl)piperidin-1-yl]propane-1,2-diol (GZ-793A), the (R)-4-methoxyphenyl-N-1,2-diol analog, and (R)-3-[2,6-cis-di(1-naphthylethyl)piperidin-1-yl]propane-1,2-diol (GZ-794A), the (R)-1-naphthyl-N-1,2-diol analog, exhibited the highest potency (K i ϳ30 nM) inhibiting VMAT2, and both analogs inhibited methamphetamine-evoked endogenous DA release (IC 50 ϭ 10.6 and 0.4 M, respectively). Thus, the pharmacophore for VMAT2 inhibition accommodates the N-1,2-diol moiety, which improves drug-likeness and enhances the potential for the development of these clinical candidates as treatments for methamphetamine abuse.

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

“…Accordingly, we also examined the ability of these compounds to inhibit the plasmalemma transporters, DAT and SERT (Tables 1 and 2; Figures 3 and 4). Generally, all of the analogues in this study exhibited affinities for DAT comparable to those for both lobelane (K i = 1.05 µM) and GZ-793A (K i = 1.44 µM) 15 . Likewise, a preponderance of the compounds inhibited SERT with affinities not different from those for lobelane (K i = 3.6 µM) and GZ-793A (K i = 9.36 µM) 15 .…”

New Fluorescent Substrate Enables Quantitative and High-Throughput Examination of Vesicular Monoamine Transporter 2 (VMAT2)

“…These compounds, structurally distinct from reserpine and TBZ (Figure 2), are pursued as novel therapeutics in preclinical and clinical studies of methamphetamine abuse disorders. (16, 17) Further, high-affinity VMAT2 inhibitors represent a starting point for the development of diagnostic and imaging agents. A number of PET (Positron Emission Tomography) tracers targeting VMAT2 have been reported and examined as diagnostic tools in the context of neurological and psychiatric disorders.…”

The Vesicular Monoamine Transporter-2

“…Emerging from the in vitro pharmacological evaluation of this series of analogs was ( R )-3-[2,6- cis -di(4-methoxyphenethyl)piperidin-1-yl]propane-1,2-diol (GZ-793A; Fig. 2.1), a potent, VMAT2-selective, drug-like lead (Horton, Siripurapu, Zheng, Crooks, & Dwoskin, 2011). GZ-793A was a potent competitive inhibitor of DA uptake at VMAT2, exhibiting a K i value of 29 nM and an I max of 86%.…”

“…For example, GZ-793A was 50-fold selective for inhibiting VMAT2 function over DAT or SERT, suggesting that GZ-793A would have low abuse liability at relevant doses. Importantly, GZ-793A inhibited METH-evoked DA release from superfused striatal slices (Horton, Siripurapu, Zheng, et al, 2011), and GZ-793A reduced the duration of the METH-induced increase in extracellular DA in nucleus accumbens in microdialysis studies (Meyer et al, 2013). Taking a more molecular approach, GZ-793A was found recently to inhibit METH-evoked DA release from isolated striatal synaptic vesicles via a surmountable allosteric inhibition and to interact with VMAT2 at several distinct sites on the protein, both extravesicular and intravesicular (Horton, Nickell, Zheng, Crooks, & Dwoskin, 2013).…”