Triple reuptake inhibitors

Triple reuptake inhibitors (TRIs), which increase DA levels in addition to serotonin and NE, are expected to be as efficacious as monoamine oxidase inhibitors (MAOIs) without being limited by the same side effects and dietary restrictions that accompany MAOI use. The rationale for including DAT inhibition is partially based on the well-established role of dopaminergic systems in motivation and reward. Anhedonia and lack of interest, which are core symptoms of MDD, result from dopaminergic impairment in corticolimbic areas, and depressed patients have been shown to have decreased DA release by nerve terminals in the mesolimbic system

  • 14]. TRIs may also have a faster onset of action in addition to increased efficacy
  • 15]. Animal models demonstrate sensitization of the dopaminergic response after chronic treatment with desipramine, and the time interval required to effect this increased sensitivity may contribute to the lag time in achieving therapeutic anti-depressant response.

The TRIs DOV-216303, (rac)-3, and DOV-21947, ( + )-3, are undergoing clinical development. Inhibition of tritiated amine uptake by human recombinant transporters expressed in HEK cells by DOV-216303 was reported to be IC50 = 13.8, 20.3, and 78 nM for SERT, NET, and DAT, respectively [15]. The corresponding IC50 values for DOV-21947 are 12.3 nM (SERT), 22.8 nM (NET), and 96 nM (DAT) [15]. Both compounds were orally active in the forced swim test. DOV-216,303 has been shown to be safe and tolerated in normal human volunteers [16], and was reported to show efficacy in Phase II clinical trials [17]. DOV-21947 has also been reported to be well tolerated with no dose-limiting side effects in initial Phase I trials.



Similar inhibition of the three transporters was reported for bicyclic compound 4, which blocked the uptake of tritiated amines in synaptosomes (1C50 = 9, 28, and 86 nM at SERT, NET, and DAT, respectively) [18]. The methylated analog 5 showed comparable activity (IC50 = 9 nM for SERT, 25 nM for NET, and 76 nM for DAT). Both compounds were active in assays confirming in vivo TRI, but no information on antidepressant activity in animal models was reported.

An approach to a faster-acting antidepressant that received much attention over the past decade is the combination of SERT inhibition with 5-HT1A receptor antagonism. Activation of somatodendritic 5-HT1A autoreceptors by increased 5-HT levels (produced from an SSRI) causes a reduction in neuronal firing until the autoreceptors desensitize. The length of time required for this process of desensi-tization has been correlated with the time required to reach clinically therapeutic effects (typically 2-4 weeks) with SSRIs. Antagonism of the 5-HT1A autoreceptor would block the negative feedback mechanism on neuronal firing, so that the effects of the SSRI would be seen more rapidly.

Efforts to identify a single molecule possessing both SSRI and 5-HT1A antagonist activity have been revealed in a number of publications over the last few years. Compounds utilizing pindolol as a starting point are exemplified by compound 6 (5-HT1A K; = 14.35 nM, SERT K = 0.86 nM), which elevated rat hypothalamic 5-HT levels to 713% of baseline (measured by microdialysis) after acute dosing at 10mg/kg, p.o. [19].

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