Dwoskin Emerging Targets and Therapeutics in the Treatment of Psychostimulant Abuse

1. Auflage 2014
ISBN: 978-0-12-420177-4
Verlag: Elsevier Science & Techn.
Format: EPUB
Kopierschutz: 6 - ePub Watermark

E-Book, Englisch, Band Volume 69, 656 Seiten

Reihe: Advances in Pharmacology

This new volume of Advances in Pharmacology presents the emerging targets and therapeutics in the treatment of psychostimulant abuse. With a variety of chapters and the best authors in the field, the volume is an essential resource for pharmacologists, immunologists and biochemists alike. - Contributions from the best authors in the field - An essential resource for pharmacologists, immunologists, and biochemists

Autoren/Hrsg.

Dwoskin, Linda P.

Leseproben

Chapter Two The Vesicular Monoamine Transporter-2
An Important Pharmacological Target for the Discovery of Novel Therapeutics to Treat Methamphetamine Abuse
Justin R. Nickell *; Kiran B. Siripurapu *; Ashish Vartak *; Peter A. Crooks *; Linda P. Dwoskin †,1    * College of Pharmacy, University of Kentucky, Lexington, Kentucky, USA
† Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky, USA
1 Corresponding author: email address: [e-mail] 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. Keywords Lobeline Lobelane GZ-793A AV-2-192 Methamphetamine VMAT2 Abbreviations AV-2-192 cis-2,5-di(2-benzyl)-pyrrolidine AV-2-197 1-methyl-cis-2,5-di(2-benzyl)-pyrrolidine CNS central nervous system CHO Chinese hamster ovary CPP conditioned place preference DA dopamine DAT dopamine transporter DTBZ dihydrotetrabenazine DOPAC dihydroxyphenylacetic acid GZ-793A (R)-3-[2,6-cis-di(4-methoxyphenethyl)piperidin-1-yl]propane-1,2-diol METH methamphetamine MTD meso-transdiene MLA methyllycaconitine MAO monoamine oxidase MPP+ 1-methyl-4-phenylpyridinium MPTP N-methyl-1,2,3,6-tetrahydropyridine NIC nicotine nAChR nicotinic acetylcholine receptor SERT serotonin transporter TBZ tetrabenazine UKMH-105 (3Z,5E)-3,5-bis(2,4-dichlorobenzylidene)-1-methylpiperidine UKMH-106 (3Z,5Z)-3,5-bis(2,4-dichlorobenzylidene)-1-methylpiperidine VMAT vesicular monoamine transporter VMAT2 vesicular monoamine transporter-2 1 Methamphetamine Addiction
Psychostimulant abuse is an escalating problem, with 100,000 new methamphetamine (METH) users in the United States each year (Drug and Alcohol Services Information System (DASIS, 2008)). Methamphetamine use poses significant health risks, including long-term neuronal damage and concomitant deleterious effects on cognitive processes, such as memory and attention (Nordahl, Salo, & Leamon, 2003). The problem is complicated by the fact that treatment centers lack an effective means to combat its abuse (DASIS, 2008). Despite the serious consequences of METH use, there are currently no approved therapeutics available for those individuals suffering from METH addiction. Increasing emphasis has been placed on identifying the underlying mechanisms of METH action and relevant pharmacological targets for the development of novel therapeutic agents to treat METH addiction. 2 Methamphetamine: Mechanism of Action
Methamphetamine (Fig. 2.1), a powerful central nervous system (CNS) stimulant, exerts its pharmacological and behavioral effects through alterations in the brain dopaminergic reward circuitry, which is generally accepted as responsible for the rewarding effects of drugs of abuse (Di Chiara et al., 2004; Koob, 1992; Wise & Bozarth, 1987; Wise & Hoffman, 1992). Methamphetamine self-administration and conditioned place preference (CPP) in rodents are gold-standard assays used to demonstrate the reinforcing and rewarding effects of this drug (Hart, Ward, Haney, Foltin, & Fischman, 2001; Xu, Mo, Yung, Yang, & Leung, 2008; Yokel & Pickens, 1973). Amphetamines (including METH) enter dopaminergic presynaptic terminals by acting as substrates for the plasmalemma dopamine transporter (DAT) and by diffusion through the plasmalemma (Fig. 2.2; Johnson, Eshleman, Meyers, Neve, & Janowsky, 1998; Sulzer et al., 1995). Once inside the presynaptic terminal, amphetamines elicit the release of vesicular dopamine (DA) stores into the cytosol through an interaction with reserpine sites on the vesicular monoamine transporter-2 (VMAT2) protein (Ary & Komiskey, 1980; Liang & Rutledge, 1982; Peter, Jimenez, Liu, Kim, & Edwards, 1994; Philippu & Beyer, 1973; Pifl, Drobny, Reither, Hornykiewicz, & Singer, 1995) and via disruption of the vesicular proton gradient as a consequence of its weak basicity and high lipophilicity (Barlow & Johnson, 1989). Amphetamines promote DA release from synaptic vesicles into the cytosol of the dopaminergic presynaptic terminal, redistributing DA stores and increasing cytosolic DA concentrations (Pifl et al., 1995; Sulzer et al., 1995), and inhibit DA uptake from the cytosol by VMAT2 (Brown, Hanson, & Fleckenstein, 2000, 2001; Fleckenstein, Volz, Riddle, Gibb, & Hanson, 2007). As amphetamines also inhibit the activity of the mitochondrial enzyme monoamine oxidase (MAO), the elevated concentrations of cytosolic DA are not subjected to metabolism (Mantle, Tipton, & Garrett, 1976). With increased cytosolic DA concentrations, DA is available for release into the synaptic cleft via reversal of DAT (Ary & Komiskey, 1980; Fischer & Cho, 1979; Liang & Rutledge, 1982; Sulzer et al., 1995). Enhanced DA release and increased stimulation of postsynaptic DA receptors that follows lead to the rewarding effects and high degree of abuse liability associated with these psychostimulant drugs (Carr & White, 1983; Hiroi & White, 1991; Hoebel et al., 1983; Lyness, Friedle, & Moore, 1979; Wise & Bozarth, 1987). Furthermore, the demonstration that heterologous VMAT2 knockout mice exhibit reduced amphetamine conditioned reward, enhanced amphetamine locomotion, and enhanced sensitivity to amphetamine also indicates that VMAT2 plays a critical role in mediating the behavioral effects of this drug of abuse (Takahashi et al., 1997; Wang et al., 1997). Although the effects of METH on VMAT2 are not the only mechanism responsible for its behavioral effects, we have considered VMAT2 as a key pharmacological target for developing pharmacotherapies to treat psychostimulant abuse (Dwoskin & Crooks, 2002), because this protein is an essential cellular component contributing to the increased extracellular DA concentrations produced by the actions of METH. Figure 2.1Chemical structures. Tetrabenazine (TBZ) is a benzoquinolizine compound that reversibly inhibits VMAT2 function. Lobeline is a lipophilic, nonpyridino alkaloid present in Lobelia inflata....