Development of Antidepressant Drugs

Abstract

Active uptake processes have been described for the monoaminergic neurotransmitters including serotonin (5-hydroxytryptamine, 5-HT), norepinephrine (NE) and dopamine (DA) in nervous tissues (Whitby, Axelrod, and Weil-Malherbe, 1961; Burgen and Iverson, 1965; Iverson, 1971). The uptake of 5-HT and NE in brain tissues has been the target sites in our search of selective inhibitors, which may have therapeutic potential for treatment of depressive disorders (Wong et al., 1974; 1975a; 1993a). Fluoxetine [Prozac], a member of the substituted phenoxyphenylpropylamines, was the first selective 5-HT uptake inhibitor to appear in the scientific literature (Wong et al, 1974) and has served as a useful tool to establish the physiological role of 5-HT neurons and a reference of pharmacological responses indicative of an enhanced transmission of 5-HT neurons (Fuller and Wong, 1977; Wong and Fuller, 1987; Wong and Murphy, 1989; Fuller and Wong, 1990). After its introduction in 1988, fluoxetine (Prozac) has become a major antidepressant drug in the United States and in many countries (Beasley et al., 1990; Boyer and Feighner, 1991a). In the U.S., two other selective 5-HT uptake inhibitors, sertraline and paroxetine, have been introduced as antidepressant drugs. In this article, we present some of the background which attracted our attention, and some studies on the chemical series of phenoxyphenylpropylamines and the enantiomers of fluoxetine and its major metabolite norfluoxetine as inhibitors of 5-HT and NE uptake in vitro. We also present the consequences of 5-HT reuptake inhibition in vivo, and the contrast between the classical tricyclic antidepressant drugs and the newly developed selective 5-HT reuptake inhibitors in terms of their interaction with receptors of neurotransmitters.