Development of a GABAergic treatment for substance abuse using PET

Abstract

Development of an effective treatment for substance abuse relies on a better understanding of the nature of the brain reward circuitry and neurotransmitter systems regulating the mechanisms responsible for drug abuse, addiction, and dependence. The use of positron emission tomography (PET) enables the direct assessment of pharmacokinetic and pharmacodynamic events in vivo. We demonstrated that administration of gamma-vinyl gamma aminobutyric acid (GVG, vigabatrin), acting through potentiation of GABAergic tone, leads to decreases in brain extracellular dopamine concentrations as measured with PET and in vivo microdialysis. This knowledge, combined with the notion that addictive drugs share the ability to stimulate dopaminergic neurotransmission, suggests a novel GABAergic strategy for the treatment of substance abuse. Over the past several years PET and in vivo microdialysis, combined with an array of behavioral tests, have demonstrated the potential utility of this approach. Taken together, our data support the use of vigabatrin for the treatment of multiple drug addictions. Drug Dev. Res. 59:240-248, 2003.

Racemic gamma vinyl‐GABA (R,S‐GVG) blocks methamphetamine‐triggered reinstatement of conditioned place preference

“…R,S-GVG irreversibly inhibits GABA-transaminase, the enzyme responsible for the catabolism of GABA (Jung et al 1977). This method of pharmacologically enhancing GABAeric transmission effectively decreases drug-induced increases in nucleus accumbens dopamine (Gerasimov and Dewey 2003). Further, using in vivo microdialysis techniques in freely moving animals previously paired to cocaine, R,S-GVG blocked cue-triggered increases in nucleus accumbens dopamine (Gerasimov et al 2001).…”

Following an ISES Lead: The First Examples of Asymmetric Ni(0)-Mediated Allylic Amination

“…α-Vinyl amino acids are potential inactivators of pyridoxal phosphate (PLP) enzymes . “Suicide substrates” bearing this vinylic trigger include the natural product l -vinylglycine and the anti-epileptic drug ( S )-vigabatrin (γ-vinyl-GABA), which may also have potential to treat substance abuse . This has led to considerable synthetic activity toward these targets. − Among the most efficient and stereocontrolled approaches to appear are transition-metal-mediated allylic amination routes by Hayashi, Alper, Trost, and Overman …”

“…Given the importance of vigabatrin, , we next set out to examine the Ni(0)-mediated transformation 19 → 20 , which would serve as a formal synthesis of the drug. Note that substitution of a CH 2 for the bridging O means that an N-PMP amidate replaces the N-PMP carbamate as the formal nitrogen nucleophile.…”

Synthesis of Quaternary Amino Acids Bearing a (2‘Z)-Fluorovinyl α-Branch: Potential PLP Enzyme Inactivators

“…Quaternary, α-vinyl amino acids (AA's) are potential mechanism-based inactivators of pyridoxal phosphate (PLP) dependent enzymes, particularly amino acid decarboxylases (AADC's). , The “vinylic trigger” is also found in the naturally occurring PLP-enzyme inactivator vinylglycine and in the anti-epileptic drug vigabatrin (γ-vinyl-GABA), which has gained attention more recently for its potential application in the treatment of substance abuse . Elegant work by Silverman and John has elucidated the mechanism by which the vinylic trigger in vigabatrin functions to inactivate GABA transaminase. , Both electrophilic (Michael addition) and nucleophilic (Metzler-type enamine-PLP aldimine condensation) pathways are operative, each of which follows from the normal first two enzymatic steps (transaldimination/γ-proton abstraction).…”