The Vesicular Monoamine Transporter-2

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.

Mechanisms of amphetamine action illuminated through optical monitoring of dopamine synaptic vesicles in Drosophila brain

“…These data are consistent with work by Dwoskin and colleagues who have developed inhibitors of methamphetamine behavioural actions using lobeline analogues. During their structure-driven pre-clinical studies, this group recognized that the drugs shared the common property of being VMAT blockers 45 . Comparable behavioural effects against methamphetamine were also observed with the VMAT2 blocker tetrabenazine, but this drug shows only modest selectivity for VMAT2 over DAT 46 .…”

SLC transporters as therapeutic targets: emerging opportunities

“…Other VMAT2 inhibitors are in clinical development, including NBI-98854 (developed by Neurocrine Biosciences), which is in Phase III trials for dyskinesia (ClinicalTrials.gov identifier: NCT02274558; note that all trials cited in this article are from this database (see Databases)) and a natural product, lobeline (developed by Yaupon Therapeutics), which is in Phase II trials for the treatment of attention-deficit hyperactivity disorder in adults (NCT00664703). VMAT2 inhibitors may also be developed for the treatment of psychostimulant abuse and addiction 106 .…”

Argon blocks the expression of locomotor sensitization to amphetamine through antagonism at the vesicular monoamine transporter-2 and mu-opioid receptor in the nucleus accumbens

“…Amphetamine is a substrate for the dopamine transporter and the vesicular monoamine transporter-2, 37 , 38 , 39 , 40 , 41 which is considered an important pharmacological target for the treatment of amphetamine drug abuse. 42 Once bound, amphetamine increased carrier-mediated dopamine release by reversing the dopamine transporter, 41 , 43 , 44 , 45 and further reduced depolarization-dependent dopamine release attributable to synaptic vesicle exocytosis by redistributing dopamine from synaptic vesicles to the neuronal cytoplasm through inhibition of the vesicular monoamine transporter-2, 45 , 46 , 47 , 48 Interestingly, both amphetamine and the inert gases including argon are well known to penetrate cell membranes through lipophilic diffusion. 49 , 50 , 51 In addition, the inert gases also bind to proteins either within the active site(s) of the proteins or within hydrophobic pockets or cavities located close to the active site(s), thereby producing direct inhibition of protein function or conformational changes critical for protein function.…”