Defense Date


Document Type


Degree Name

Doctor of Philosophy


Pharmaceutical Sciences

First Advisor

Richard A. Glennon


The khat plant, catha edulis, has been abused for some time in the Middle East and the African horn for its short-term stimulant effects. However, it was not until 1975 when cathinone, β-ketoamphetamine, was identified as the major stimulant component of khat. Structural analogues of cathinone, synthetic cathinones, are new psychoactive substances available on the clandestine market of numerous countries including the USA. Abuse of these new illicit stimulants is a worldwide growing health concern which necessitates the investigation of the pharmacological properties of these new drugs of abuse. The abuse liabilities of these compounds seem to be related to the three major monoamine transporters (MATs): the dopamine, norepinephrine, and serotonin transporters (DAT, NET, and SERT, respectively). Synthetic cathinones act as either releasing agents by stimulating the release of the presynaptic neuronal content of neurotransmitters, or as reuptake inhibitors by inhibiting normal physiological reuptake of neurotransmitters from the synaptic cleft. Bupropion (DAT/NET reuptake inhibitor) is clinically prescribed for the treatment of depression and smoking cessation, whereas its closely related cousin, cathinone (DAT/NET releasing agent), is a drug of abuse. Deconstruction of bupropion (i.e., a stepwise conversion – or structural transition – of bupropion to cathinone) and investigation of the actions of the deconstructed analogues at the three major MATs showed that the steric bulk at the terminal amine controls the molecular mechanisms of these compounds at MATs (i.e. reuptake inhibition versus substrate-induced release). This study also concluded that bupropion is abused, because it is a cathinone derivative. Methcathinone (MCAT), N-methylcathinone, (DAT/NET releasing agent) is a recreational street drug and a US Schedule I substance; however, new MCAT analogues are continually appearing on the clandestine market to circumvent prosecution under the Controlled Substance Analog Enforcement Act. We investigated the actions and structure-activity relationships of a series of 3-substituted MCAT analogues at MATs and their quantitative structure-activity relationships to determine the physicochemical properties of the 3-position substituents important for the releasing actions of these compounds. This study indicated that the steric bulk of the 3-position substituents controls the selectivity of these compounds at MATs.


© Abdelrahman R. Shalabi

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Available for download on Tuesday, December 13, 2022