UC Davis

AbstractFrom the first reports of chewing coca leaves in 3000 B.C to the first isolation of atropine in 1832, tropane alkaloids are an integral class of natural products studied in chemistry, biology, and medicine. The importance of this alkaloid family is expressed in more than 5500 publications as well as the tropane moiety being ranked 15th in most frequently used nitrogen heterocycles in U.S. FDA approved drugs. More recently, scopolamine has demonstrated efficacy in a few small clinical trials for major depressive disorder (MDD) and bipolar disorder (BPD). This finding in humans has been directly correlated to scopolamine’s ability to induce neuronal plasticity in rat cortical neurons. Roughly 17.3 million American adults, or 7.1% of the U.S population age 18 and older have MDD. Around 2.8% or 9.3 million American adults have bipolar disorder. Current treatments for MDD and BPD revolve around either the use of psychoplastogens selective for the serotonin 2 receptors, or selective serotonin reuptake inhibitors (SSRIs) and selective norepinephrine reuptake inhibitors (SNRIs). Downsides to these treatments include the potential to induce hallucinations associated with many current psychoplastogens, and slow-acting nature of SSRIs and SNRIs). While scopolamine has potential as a therapy for MDD and BPD, it still poses risks due to its ability to induce delirium, as well as its potent anticholinergic properties. There were two major questions that arose at the beginning of my doctorate: One, are there other tropane alkaloids that hold these psychoplastogenic effects like scopolamine without the negative side effects? Two, can we synthesize a set of novel, unnatural tropane analogs that can induce neuroplasticity along with engineering out the anticholinergic properties from the tropane pharmacological skeleton? To answer these two questions, I developed a short divergent synthesis with the capability for late-stage diversification targeting the two main tropane alkaloid chemotypes. The tropane alkaloids synthesized were then tested in several biological assays to determine that they were not serotonergic ligands, but still induced plasticity.