Methcathinone (MCAT) is the β-ketone analog of methamphetamine, and like its amphetamine analog, MCAT functions as a monoamine releaser that selectively promotes the release of dopamine (DA) and norepinephrine (NE) over serotonin (5-HT). MCAT produces amphetamine-like psychostimulant effects and is classified as a Schedule I drug of abuse by the United States Drug Enforcement Administration (DEA). Recently, synthetic MCAT analogs have emerged as designer drugs of abuse in Europe and the United States and have been marketed under deceptively benign names like “bath salts” in an attempt to evade legal restriction. These dangerous, recently emergent and novel drugs of abuse display varying selectivity to promote release of DA/NE vs. 5-HT, and selectivity for DA neurotransmission is believed to correlate with abuse liability. The goal of this dissertation was to conduct preclinical research to examine structural determinants of abuse-related behavioral and neurochemical effects produced by a series of synthetic MCAT analogs. Specifically, this project focused on one feature of the methcathinone scaffold: the para substituent of the benzene ring. A series of six novel MCAT analogs will be examined to evaluate how physicochemical parameters (steric, Es; electronic, σp; lipophilic, πp) of the para substituent influence in vitro monoamine transporter selectivity as well as in vivo neurochemical and behavioral effects. Results from this body of work implicate steric factors as being particularly important in determining a compound’s abuse-related neurochemical and behavioral effects. Thus, these data not only offer an improved understanding of the mechanism of abuse-related drug effects produced by synthetic MCAT analogs, but also help in the generation of homology models of the human DA and 5-HT transporters (DAT and SERT, respectively).

In the last few years, there has been continued concern about synthetic drug abuse in both the United States and worldwide. Small adjustments in drug compound structure often allow synthetic drug makers to manufacture a legal product that can produce the same highs as illegal counterparts. Unfortunately, this is happening faster than the government can outlaw the drug compounds, and a wide variety of synthetics are now appearing on the street. This study evaluated the effects on the human serotonin transporter of six different 4-para substituted methcathinone compounds. Using a Xenopus oocyte model, the efficacy of each MCAT analogue at hSERT was calculated by applying the Hill equation to the oocyte data. This study suggests that volume, size, and steric bulk of the compound may generally influence efficacy at hSERT in a direct manner, but that other factors, like lipophilicity, may also play an important role in potency at the transporter.

Hierdie studie fokus op hoe persone wat van dwelms afhanklik is of was, hulle identiteit sien. Daar is ’n bekende diskoers wat sê: “Een keer ’n verslaafde, altyd ’n verslaafde.” Hierdie diskoers impliseer dat afhanklikheid deel van ’n persoon se identiteit word. In my studie poog ek om hierdie diskoers te dekonstrueer. Die AA (Alkoholiste Anoniem) se twaalf-stap-program word bestudeer. In hulle eerste stap word daar van persone wat van ’n chemiese stof afhanklik is, verwag om te erken dat hy/sy ’n afhanklike is. Hierdie erkenning van die AA se eerste stap, het ’n direkte invloed op persone wat van dwelms afhanklik is of was. Saam met die medenavorsers, word daar gepoog om ’n alternatiewe manier te vind om na afhanklikheid en identiteit te kyk. Hiermee saam speel die Christendom en ’n persoon se Godsbegrip ’n groot rol. Die Christendom het verskillende sieninge oor afhanklikheid en sonde. Hierdie studie poog nie om die sondebegrip van die Nuwe Testament te bestudeer nie, aangesien hierdie nie ’n Nuwe-Testamentiese studie is nie. Hoe God en die medenavorsers sonde verstaan, speel ’n rol in die begrip van hulle identiteit. Die narratiewe benadering maak van metafore gebruik. Hierdie studie gebruik die metafoor van ’n draak. Aanvanklik is dit ’n gevreesde draak wat persone wat afhanklik van dwelms is of was, wil verslind en ’n direkte impak het op hulle identiteit. ‘n Nuwe metafoor het ontwikkel. Die animasiefilm, “How to train your dragon,” is as vertrekpunt gebruik om ’n nuwe metafoor te ontwikkel waar die draak steeds gevaarlik is, maar getem kan word. Deur sekere aanpassings te maak, kan persone wat afhanklik is of was van dwelms, die draak beheer. Hierdie nuwe metafoor gee ook ’n nuwe identiteit aan die persoon wat afhanklik is of was van dwelms. Afhanklikheid word nie meer as deel van ’n persoon se identiteit beskou nie aangesien die hantering van die draak ’n nuwe perspektief in die lewe van hierdie persoon gee. In my studie maak ek van kwalitatiewe navorsing gebruik en beweeg ek vanuit die oogpunt van ’n postfundamentele Praktiese Teologiese benadering. / Thesis (PhD)--University of Pretoria, 2017. / Practical Theology / PhD / Unrestricted