At Eli Lilly in the 1960s, Schmiegel and Bryan Molloy, with the help of David Wong, searched for a compound to combat depression. Because depression and similar psychiatric disorders are associated with reduced serotonin levels, they focused their approach on prohibiting serotonin reuptake. During a regular nerve signal transmission, a neurotransmitter such as serotonin travels from a presynaptic neuron to a postsynaptic neuron; the neurotransmitter returns to the presynaptic neuron after fulfilling its function, the reuptake process. Therefore, slowing and diminishing serotonin reuptake boosts serotonin levels in the brain.
The scientists based their search on the template of the antihistamine drug diphenhydramine hydrochloride, commonly known as Benadryl. After many failures, the research team synthesized a group of compounds called aryloxyphenylpropylamines. Upon testing, a member of the group, fluoxetine hydrochloride, proved to affect only the neurotransmitter serotonin. This compound became the first selective serotonin reuptake inhibitor (SSRI) and the active ingredient in the vastly popular and effective drug Prozac.