Despite the structural similarity of the norepinephrine, serotonin, and dopamine transporters, synthesis of bioavailable and safe molecules which appreciably inhibit all three transporters has been challenging [46
]. Additionally, the optimal selectivity at the three transporter sites is unknown, and it is plausible that different potency ratios mean different clinical effects. Two families of compounds in development are analogs of the dual reuptake inhibitors milnacipran and venlafaxine. In particular, racemic analogs of venlafaxine referred to as PRC025 and PRC050 are highly potent at human norepinephrine (NE), serotonin (SER), and dopamine (DA) transporters and inhibit the reuptake of these monoamines into rat brain synaptosomes [39
]. These compounds exhibited antidepressant-like characteristics equal to imipramine in well-accepted rat models of antidepressant effect; both PRC025 and PRC050 increased time spent swimming and reduced time spent immobile in the forced swim test and reduced time spent immobile in the tail suspension test [39
]. Several milnacipran derivatives have been developed in search of molecules with more potent N-methyl-D-aspartic acid (NMDA) antagonism [23
,42 cited in 37]. More recently, analogs have been synthesized to evaluate their relative monoamine transporter inhibition potency and selectivity. An isomer of one such analog (-)-8h functions as a triple reuptake inhibitor in vitro
]. To date, animal or human antidepressant studies have not been published with this compound.
DOV Pharmaceutical, Inc. has developed triple reuptake inhibitors from a class of azabicyclohexanes chemically related to bicifadine. Three of these compounds (DOV 216,303, DOV 21,947, and DOV 102,677) have been shown to block transport of human recombinant NE, SER, and DA transporters with clinically-relevant potency (Table
]. Also, all three of these compounds demonstrated antidepressant properties in rodent models; 21,947 reduced immobility during forced swim test and tail suspension test [45
], 102,677 reduced immobility during forced swim test [34
], and 216,303 reduced immobility during forced swim test and reversed tetrabenazine-induced ptosis [44
]. Human studies with DOV 216,303 show that it is well-tolerated at clinically appropriate doses with minor gastrointestinal side effects ranging from 19-57% [4
,]. A small citalopram-controlled clinical trial of DOV 216,303 (N=67) yielded significant improvements in Hamilton Depression Rating Scale (HAMD) scores in both groups at both the one-week and two-week time points, although the study lacked a placebo group [44
]. Bicifadine (1-p-tolyl-3-azabicyclo[3.1.0]hexane) itself has been pharmacologically characterized, and it has been shown to inhibit monoamine neurotransmitter uptake by recombinant human transporters in vitro
with a relative potency of NE:SER:DA of 1:2:17 [3
]. To date, published preclinical research has focused on the potential antinociceptive properties of bicifadine [3
], although its utility as an antidepressant warrants exploration.
Summary of Characteristics and Pharmacokinetic Parameters of Triple Reuptake Inhibitors in Development
The novel triple reuptake inhibitor tesofensine (NS 2330) has not been systematically studied regarding its clinical or preclinical antidepressant effects. Similar to antidepressants [6
], this agent has demonstrated neuroprotective effects including increasing brain derived neurotrophic factor (BDNF) and neuronal proliferation in the rat hippocampus [26
It is likely that other triple reuptake inhibitors are in various developmental phases, and the current discussion of compounds in development should not be considered exhaustive. A summary of described compounds appears below in Table .