Article

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: 3.89). 03/2011; 336(3):940-51. DOI: 10.1124/jpet.110.175117
Source: PubMed

ABSTRACT 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.

0 Bookmarks
 · 
124 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: The widest distribution and the highest uptake of methamphetamine (MA) in the human body occurred in the lungs, so that more and more attention should be paid to MA-induced pulmonary toxicity. MA induces the release of serotonin, which is an important mediator in pulmonary disease. The purpose of this study is to investigate the chronic response of the lung to MA and its potential mechanism in rats. Models of the chronic toxicity of MA were established with MA of 5 mg/kg and 10 mg/kg (intraperitoneally, twice per day) for 5 weeks. It was found that the high dose of MA induced rat pulmonary toxicity: crowded lung parenchyma, thickened septum, reduced number of alveolar sacs, inflammatory cell infiltration, and pulmonary arteriolar remodeling. In addition, MA resulted in a significant increase in the lung serotonin concentration and the marked upregulation of tryptophan hydroxylase 1, vesicular monoamine transporter 2, serotonin transporter, and downregulation of monoamine oxidase-A. These findings suggest that MA induced chronic pulmonary toxicity, which is concerned with the elevated serotonin concentration in rat lungs by increased synthesis, reduced metabolism, augmented accumulation, and promoted release of serotonin.
    Human & Experimental Toxicology 03/2013; · 1.41 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Methamphetamine abuse escalates, but no approved therapeutics are available to treat addicted individuals. Methamphetamine increases extracellular dopamine in reward-relevant pathways by interacting at vesicular monoamine transporter-2 (VMAT2) to inhibit dopamine uptake and promote dopamine release from synaptic vesicles, increasing cytosolic dopamine available for reverse transport by the dopamine transporter (DAT). VMAT2 is the target of our iterative drug discovery efforts to identify pharmacotherapeutics for methamphetamine addiction. Lobeline, the major alkaloid in Lobelia inflata, potently inhibited VMAT2, methamphetamine-evoked striatal dopamine release, and methamphetamine self-administration in rats but exhibited high affinity for nicotinic acetylcholine receptors (nAChRs). Defunctionalized, unsaturated lobeline analog, meso-transdiene (MTD), exhibited lobeline-like in vitro pharmacology, lacked nAChR affinity, but exhibited high affinity for DAT, suggesting potential abuse liability. The 2,4-dicholorophenyl MTD analog, UKMH-106, exhibited selectivity for VMAT2 over DAT, inhibited methamphetamine-evoked dopamine release, but required a difficult synthetic approach. Lobelane, a saturated, defunctionalized lobeline analog, inhibited the neurochemical and behavioral effects of methamphetamine; tolerance developed to the lobelane-induced decrease in methamphetamine self-administration. Improved drug-likeness was afforded by the incorporation of a chiral N-1,2-dihydroxypropyl moiety into lobelane to afford GZ-793A, which inhibited the neurochemical and behavioral effects of methamphetamine, without tolerance. From a series of 2,5-disubstituted pyrrolidine analogs, AV-2-192 emerged as a lead, exhibiting high affinity for VMAT2 and inhibiting methamphetamine-evoked dopamine release. Current results support the hypothesis that potent, selective VMAT2 inhibitors provide the requisite preclinical behavioral profile for evaluation as pharmacotherapeutics for methamphetamine abuse and emphasize selectivity for VMAT2 relative to DAT as a criterion for reducing abuse liability of the therapeutic.
    Advances in pharmacology (San Diego, Calif.) 01/2014; 69:71-106.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Addiction to methamphetamine (METH) is thought to be mediated by dopaminergic effects in the reward pathway in the brain via the A10 dopaminergic pathway. Herein we describe an overview of the results of the basic preclinical science undertaken to provide mechanistic insights into the action of amphetamines in general and METH in particular. A brief history of amphetamine and METH use and abuse is given, and an overview of the relevant chemical aspects of amphetamine as they relate to neurotransmitters in general is made. A review of the methods used to study the biochemical effects of METH is outlined. Finally, a focused analysis of the kinetic mechanisms of action of the amphetamines in general, and METH in particular, at the transmembrane transporters and at the intracellular vesicular storage sites is made. A description of how catecholaminergic and serotonergic nerve signaling may be altered by METH is proposed. Overall, the emphasis here is on differences in effects observed between the striatal (the A9 substantia nigral dopamine pathway) and nucleus accumbens (the A10, ventral tegmental pathway) areas of the brain following acute as well as repeated dosing and withdrawal.
    Current Drug Abuse Reviews 09/2012; 5:227-242.

Full-text (2 Sources)

Download
37 Downloads
Available from
May 27, 2014