Studies in the design and synthesis of novel selective serotonin reuptake inhibitors

Abstract

The serotonin transporter (SERT) has been the target of several modern day antidepressants with the focus on achieving selectivity over other monoamine transporters, thereby minimising the side effects observed in the older generation of tricyclic antidepressants. Selective serotonin reuptake inhibitors (SSRIs) have shown to be among the most effective treatment of depression currently available. However they are known to have several considerable disadvantages over other classes of antidepressant drugs, such as a slow onset of action (often taking several weeks), headaches, nausea and sleep disruption. With this in mind researchers are constantly trying to improve the profile of compounds used to treat depression. The main aim of this thesis is to design, synthesise and biochemically test a series of novel compounds in the search for a selective SERT inhibitor, from which further work in derivatising the most active skeletal structure may proceed. In chapter one the biochemical nature of depression and neurotransmission, including the role played by the serotonin transporter, with the main focus being the monoamine theory of depression is discussed. A comprehensive range of compounds active at SERT is reviewed based on the biochemical activities imparted by the various structural properties of the ligands. Attention is also drawn to the studies carried out on the proposed active binding sites within SERT and the computational models produced as a result.