Nearly all antidepressants currently prescribed are selective serotonin or dual serotonin  - norepinephrine reuptake inhibitors (SSRIs and SNRIs respectively), working through blocking SERT (serotonin transporter) or both SERT and NET (norepinephrine transporter) in the brain. However, about 30-40% of patients do not adequately respond to treatment with SSRIs or SNRIs. Adding a DAT (dopamine transporter) component can potentially improve the efficacy of SSRIs and SNRIs based on clinical evidence from combination studies. Triple reuptake inhibitors (TRIs) block SERT, NET and DAT simultaneously and hold promise as a new therapy for inadequately-treated depression. Here, we report a series of novel 4-bicyclic heteroaryl 1, 2, 3, 4-tetrahydroisoquinoline derivatives as TRIs. The synthesis and the Structure-Activity Relationship of this series will be presented. An advanced compound from this series, ALB 109780 (AMR-000002), exhibited substantial occupancy levels at the three transporters in both rat and mouse brain.  It also demonstrated efficacy in rodent models of depression.

4-Bicyclic heteroaryl 1, 2, 3, 4-tetrahydroisoquinoline derivatives as novel triple reuptake inhibitors

243rd National Meeting (2012)

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