Design and synthesis of selective serotonin agonists for the therapeutic treatment of obesity

The terms “Obesity Epidemic” and more recently “Globesity” have been used to communicate the enormity of the health crisis being faced by authorities across the world. The incidence of obesity in adults in the United States (U.S.) has more than doubled in the last 20 years and costs associated with obesity have been estimated by Health Authorities to have risen from $46 billion in 1990 to $147 billion in 2008. This situation is not unique to the U.S. and similar trends are being observed in many parts of the western world. Currently, there are very few therapeutic agents approved for the treatment of obesity and they are limited in their effectiveness. Bariatric surgery, or weight loss surgery, is now the preferred treatment for obesity, as it is the most successful weight loss method available. While it has increased 10-fold in both the United States and Australia over the last decade, bariatric surgery is expensive, remains high risk and its suitability as a safe long term treatment for obesity is still under evaluation. The need for safer and more effective therapeutic drugs, and how this might be achieved, is discussed during this dissertation. A general review of pharmaceutical treatments for obesity, including recently developed compounds that are under patent and in clinical trials, is undertaken. The various biological mechanisms being targeted by different research groups to treat obesity are outlined. The lessons learnt from the ill-fated use of fenfluramine as a weight loss drug are discussed. Fenfluramine was considered the best treatment for obesity in the early 1990s but was withdrawn from the market in 1997 due to major side effects that caused heart valve defects and, to a lesser extent, high blood pressure. Weight loss from fenfluramine was attributed to 5-HT2C receptor agonism and the side effects were due to 5-HT2B, and to a lesser extent 5 HT2A receptor agonism. Our research focus on the development of selective 5-HT2C receptor agonists is described in this dissertation. The development of a pharmacophore model with a secondary amine in a ring to restrict rotation is discussed, as well as the learning from the new generation of emerging drug candidates and how this can be applied to improve drug selectivity. The design and synthesis of Series 1 compounds, twenty 4 phenylpiperidines and six 4 phenyl 1,2,3,6-tetrahydropyridines aimed at increasing 5 HT2C receptor selectivity is presented. The concurrent design and preparation of a series of alkyl-4-piperidones required for the synthesis of Series 2 compounds is reported. Structural elucidation of relevant Series 1 compounds, as well as alkyl-4-piperidones using NMR spectroscopy is described. The biological test results from Series 1 indicated that 4-phenyl-1,2,3,6-tetrahydropyridines exhibited considerably stronger agonism at the 5-HT2C receptor than 4-phenypiperidines, thereby directing the choice of scaffold for Series 2. The focus for target compounds became 4 phenyl alkyl-1,2,3,6-tetrahydropyridines, and their similarity to MPTP which metabolizes to the known dopaminergic neurotoxin MPP+ is reviewed in this dissertation. The synthesis, isolation, structural characterization and biological testing of a series of 4 phenyl alkyl-1,2,3,6-tetrahydropyridines (Series 2) is described. The biological test results indicate that a number of compounds in the second series exhibit strong agonism at the 5 HT2C receptor, and weak antagonism at the 5 HT2A and 5 HT2B receptors, fulfilling the aim of the project. Possible future directions arising from this work are reviewed in the closing remarks section of this dissertation