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Discovery Of Novel Pharmacotherapeutics For Substance Use Disorders, Na-Ra Lee
Discovery Of Novel Pharmacotherapeutics For Substance Use Disorders, Na-Ra Lee
Theses and Dissertations--Pharmacy
Substance use disorders are serious health concerns in the United States. Furthermore, the National Survey on Drug Use and Health reports a continuous increase in substance use disorders in the United States during the last 10 years. However, there are not many effective pharmacotherapeutics available for substance use disorders. The current dissertation is focused on research aimed at discovering pharmacotherapeutics for substance use disorders. First part of dissertation focused on discovering methamphetamine (METH) use disorder therapeutics targeting specific mechanism of METH action on dopaminergic neurons. The second part of dissertation focused on opioids and cocaine use disorder therapeutics targeting rewarding …
Design, Synthesis, And Pharmacological Evaluation Of Three Series Of Lobelane Analogs As Inhibitors Of The Vesicular Monoamine Transporter (Vmat2), John P. Culver
Theses and Dissertations--Pharmacy
Methamphetamine (METH) abuse is a serious problem in the United States and worldwide. The reward experienced by METH users is due to the increase in extracellular dopamine (DA) concentrations caused by an interaction between METH and the DA transporter (DAT) as well as the Vesicular Monoamine Transporter-2 (VMAT2). The reward felt by users of METH leads to further use of the drug and subsequent abuse. The current project examined the ability of three novel series of lobelane analogs to interact with a binding site on the Vesicular Monoamine Transporter-2 (VMAT2) in an attempt to inhibit the effects of METH. Lobelane …
Lobelane Analogs With Various Methylene Linker Lengths And Acyclic Lobelane Analogs As Potential Pharmacotherapies To Treat Methamphetamine Abuse, Zheng Cao
Theses and Dissertations--Pharmacy
Methamphetamine interacts with vesicular monoamine transporter-2 (VMAT2) to inhibit dopamine (DA) uptake and promotes DA release from presynaptic vesicles, increasing cytosolic DA available for methamphetamine-induced reverse transport by DA transporters. By inhibiting VMAT2, lobelane, a defunctionalized, saturated lobeline analog, decreases methamphetamine-evoked DA release and methamphetamine self-administration in rats. In this dissertation structure-activity relationships around the lobelane structure were investigated on racemic lobelane analogs with varying methylene linker lengths at central piperidine ring. Affinity for dihydrotetrabenazine (DTBZ) sites on VMAT2 and for inhibition of VMAT2 function was determined to be 0.88-63 and 0.024-4.6 µM, respectively, and positively correlated. The most potent …
Discovery Of Gz-793a, A Novel Vmat2 Inhibitor And Potential Pharmacotherapy For Methamphetamine Abuse, David B. Horton
Discovery Of Gz-793a, A Novel Vmat2 Inhibitor And Potential Pharmacotherapy For Methamphetamine Abuse, David B. Horton
Theses and Dissertations--Pharmacy
Methamphetamine abuse is a serious public health concern affecting millions of people worldwide, and there are currently no viable pharmacotherapies to treat methamphetamine abuse. Methamphetamine increases extracellular dopamine (DA) concentrations through an interaction with the DA transporter (DAT) and the vesicular monoamine transporter-2 (VMAT2), leading to reward and abuse. While numerous studies have focused on DAT as a target for the discovery of pharmacotherapies to treat psychostimulant abuse, these efforts have been met with limited success. Taking into account the fact that methamphetamine interacts with VMAT2 to increase DA extracellular concentrations; the focus of the current work was to develop …