mGlu2/3 Receptor and TRD
In 2006, C.Zarate published that a single injection of the NMDA antagonist ketamine will cause rapid remission of depressive symptoms in patients suffering from treatment resistant depression (TRD).
The onset of remission was observed after just a few hours and lasted up to 7 days. In 2009, R. Dumas elucidated the mechanism of action by which ketamine confers its fast onset of anti-depressive activity as well as its long duration, hypothesizing that ketamine works through potentiation of AMPA receptors followed by downstream activation of mTOR.
Similar to ketamine, BCI-632 shows long lasting anti-depressive activity in animal models. The long lasting activity is mediated through AMPA receptor potentiation and downstream activation of mTOR. Recently, L.Monteggia showed that the rapid onset observed with ketamine is mediated through the BDNF signaling pathway. Interestingly, the anti-depressive activity of BCI-632 is blocked by K252a, a TrkB inhibitor. All these data together suggest that BCI-632 shares a common signaling pathway with ketamine and that BCI-632 may be efficacious in the treatment of TRD.
While ketamine is used in clinical practice today in select patients with TRD, it is associated with psychotic-like symptoms which limits it use. BCI-632 and its prodrugs represent an alternative approach potentially devoid of this side effect liability.