meso-Transdiene Analogs Inhibit Vesicular Monoamine Transporter-2 Function and Methamphetamine-Evoked Dopamine Release

Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536-0082, USA.
Journal of Pharmacology and Experimental Therapeutics (Impact Factor: 3.97). 03/2011; 336(3):940-51. DOI: 10.1124/jpet.110.175117
Source: PubMed


Lobeline, a nicotinic receptor antagonist and neurotransmitter transporter inhibitor, is a candidate pharmacotherapy for methamphetamine abuse. meso-Transdiene (MTD), a lobeline analog, lacks nicotinic receptor affinity, retains affinity for vesicular monoamine transporter 2 (VMAT2), and, surprisingly, has enhanced affinity for dopamine (DA) and serotonin transporters [DA transporter (DAT) and serotonin transporter (SERT), respectively]. In the current study, MTD was evaluated for its ability to decrease methamphetamine self-administration in rats relative to food-maintained responding. MTD specifically decreased methamphetamine self-administration, extending our previous work. Classical structure-activity relationships revealed that more conformationally restricted MTD analogs enhanced VMAT2 selectivity and drug likeness, whereas affinity at the dihydrotetrabenazine binding and DA uptake sites on VMAT2 was not altered. Generally, MTD analogs exhibited 50- to 1000-fold lower affinity for DAT and were equipotent or had 10-fold higher affinity for SERT, compared with MTD. Representative analogs from the series potently and competitively inhibited [(3)H]DA uptake at VMAT2. (3Z,5Z)-3,5-bis(2,4-dichlorobenzylidene)-1-methylpiperidine (UKMH-106), the 3Z,5Z-2,4-dichlorophenyl MTD analog, had improved selectivity for VMAT2 over DAT and importantly inhibited methamphetamine-evoked DA release from striatal slices. In contrast, (3Z,5E)-3,5-bis(2,4-dichlorobenzylidene)-1-methylpiperidine (UKMH-105), the 3Z,5E-geometrical isomer, inhibited DA uptake at VMAT2, but did not inhibit methamphetamine-evoked DA release. Taken together, these results suggest that these geometrical isomers interact at alternate sites on VMAT2, which are associated with distinct pharmacophores. Thus, structural modification of the MTD molecule resulted in analogs exhibiting improved drug likeness and improved selectivity for VMAT2, as well as the ability to decrease methamphetamine-evoked DA release, supporting the further evaluation of these analogs as treatments for methamphetamine abuse.

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    • "A growing body of evidence, including the current findings, demonstrates that inhibition of VMAT2 function specifically blocks METH reward (Harrod et al. 2001; Neugebauer et al. 2007; Beckmann et al. 2010). Furthermore, VMAT2 inhibition selectively reduces METHinduced striatal DA release (Miller et al. 2004; Beckmann et al. 2010; Nickell et al. 2010; Horton et al. 2011a, b), consistent with the critical involvement of DA function in reward (Berridge 2007; Wise and Rompre 1989; Everitt and Robbins 2005). The effect of GZ-793A to inhibit METH-evoked DA release is selective, since GZ-793A does not alter nicotineevoked or field stimulation-evoked striatal DA release (unpublished results). "
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