Synthesis and Evaluation of Antiaddictive Natural Products

This dissertation seeks to provide data in support of four main claims: (i) molecular targets exist that, by inducing a variety of physiological changes, bring about the subjective and reinforcing effects of drugs of abuse; (ii) when these targets are acted upon by ligands, the subjective and reinforcing effects of drugs are sometimes mitigated; (iii) such ligands sometimes come from natural sources; and (iv) these natural products can be synthesized, derivatized, and evaluated in the lab. The novel synthesis and derivatization of the Aristotelia scaffold generated a library of analogs which deepened our understanding of its SAR at the α3β4 nAChR. The extraction and semi-synthetic derivatization of voacangine enabled the access of several iboga alkaloids which were evaluated for their ability to bind to DAT and SERT. Together, the synthesis and evaluate of these antiaddictive natural products contributed to basic science research that may lay the foundation for the development of a first-in-class drug to treat PSUD.