Design and synthesis of potential serotonin-selective reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors for the treatment of depression.

Depression is a common disease characterized by feelings of deep sadness, guiltiness, loss of interest in once pleasurable activities, and thoughts of self-harm among others. Affecting an estimated 121 million people worldwide, depression does not discriminate on the basis of gender, age, culture or social status. Research shows a diminished concentration of the neurotransmitters serotonin and norepinephrine in the synapses between neurons of depressed patients. For this reason, and with the advent of new and more powerful computational tools, two families of compounds called Serotonin-Selective Reuptake Inhibitors (SSRIs) and Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs) have been developed. These compounds block the reuptake process of serotonin and norepinephrine into the presynaptic neuron in order to increase the amount of these neurotransmitters in the synapses. Although these drugs have been successful in the treatment of depression, the side effects that accompany them are the major reason for patients to abandon treatment before completion. One of these side effects is sexual dysfunction, which has been associated with the serotonin receptor 2A (5-HT2A). In this project, a series of compounds based on the molecular structures of fluoxetine (Prozac ®) and 4-[(3-fluorophenoxy)phenylmethyl)piperidine were coupled with chemical entities that are known to possess activity against the 5-HT2A receptor by chemical synthesis. It is anticipated that hybrid molecules will reduce the sexual dysfunction side effect without significantly affecting the antidepressant activity. Since serotonin is known to act as a growth factor, the synthesized compounds were tested for activity against several human cancer cell lines. A second project involved progress towards the synthesis of a new compound designed to selectively target the tumor microenvironment. This compound incorporates structural features of both combretastatin A4 and the bioreductive agent tirapazamine. Certain members of the combretastatin series of natural products demonstrate tumor cytotoxicity and damage tumor vasculature. Since many solid tumors are hypoxic, bioreductive entities such as tirapazamine are viable treatment agents.