The Effects of Synthetic Cathinone Chirality on Pharmacodynamics and Pharmacokinetics and Its Implications for Forensic Toxicology

As the attention in the United States is focused on the "opioid epidemic," the rise in the use and number of overdose deaths associated with stimulant drugs risks being overshadowed. The novel psychoactive substances being abused includes the beta-keto analogs of the amphetamine-type stimulants known as synthetic cathinones. Many synthetic cathinones, including methcathinone, contain a stereocenter at the alpha carbon. This introduces chirality to the molecule such that two spatial orientations of the molecule exist, and this has the potential for significant impacts to the interpretation of analytical data by the forensic toxicologist due to pharmacokinetic and pharmacodynamic differences between enantiomeric forms. The current research on synthetic cathinones largely focuses on racemic mixtures and typically does not distinguish between enantiomeric forms. This research will examine racemic methcathinone and its two enantiomers individually, as well as two novel compounds where chirality is removed by making substitutions upon the alpha carbon of the molecule. The researcher will accomplish three main objectives: (1) abuse liability will be assessed using intracranial self-stimulation in a rat model for each compound (2) analytical methodology will be developed and validated according to the Scientific Working Group for Forensic Toxicology (SWGTOX) guidelines for the stereospecific identification of these synthetic cathinones and their potential biomarkers in biological matrices and (3) the pharmacokinetics of these cathinonest specifically the metabolism, tissue distribution, and elimination, will be examined with respect to the stereochemistry of the molecules. These three research aims will provide the scientific and forensic communities with a greater understanding of synthetic cathinones and their stereochemistry to be used in forensic toxicological analysis, including providing both practical methods for analysis as well as pharmacological relationships to be used in the interpretation of toxicological findings in the context of legal investigations. This interdisciplinary project involves the collaboration of the Virginia Commonwealth University Departments of Forensic Science and Pharmacology and Toxicology to generate a robust set of data involving analytical chemistry and behavioral pharmacology. This research is anticipated to result in multiple publications in peer-reviewed journals and presentations at scientific conferences, as well as a doctoral dissertation. Note: This project contains a research and/or development component, as defined in applicable law," and complies with Part 200 Uniform Requirements - 2 CFR 200.210(a)(14). ca/ncf