Fluoxetine, a Highly Selective Serotonin Reuptake Inhibitor: A Review of Preclinical Studies

Abstract

The chemical structure of fluoxetine, (±)-N-methyl-3-phenyl-3-[(α,α,α-trifluoro-p-tolyl)oxy]propylamine, as shown in Fig. 1, lacks the three-fused ring system contained in tricyclic antidepressant drugs (TCAs) such as imipramine and amitriptyline. The p-trifluoromethyl substituent on the phenoxy ring of fluoxetine is an important determinant of its potency and its specificity as a serotonin-uptake inhibitor, e.g. the analogue having an o-trifluoromethyl substituent on that ring is only about one-hundredth as potent as fluoxetine in inhibiting serotonin uptake (Wong et al, 1975a). Nisoxetine (Wong et al, 1975b) and tomoxetine (Wong et al, 1982) are analogues differing from fluoxetine only in having an o-methoxy or an o-methyl substituent respectively, in place of the p-trifluoromethyl substituent on the phenoxy ring. Nisoxetine (LY94939) and tomoxetine (LY 139603) are potent and highly selective inhibitors of norepinephrine uptake (Wong et al, 1975b, 1982), differing strikingly from fluoxetine in specificity of uptake inhibition. Fluoxetine has been shown to be a potent and selective inhibitor of serotonin uptake in laboratory animals; it is orally effective and has a long duration of action. This compound has been a valuable pharmacological tool to study the mechanisms of serotonergic neurotransmission and physiological functions of brain serotonin neurons (Fuller & Wong, 1977; Wong et al, 1985a; Fuller & Wong, 1987). The present paper summarises some of the pre-clinical studies which have characterised fluoxetine as a selective inhibitor of serotonin uptake.