A new compound, B11, shows promise as a rapid-acting antidepressant in preclinical models. Unlike existing fast-acting treatments such as esketamine and psychedelics, which carry risks of psychotic side effects and substance abuse, B11 activates the TrkB-CREB signaling axis without interfering with targets linked to those side effects. B11 readily crosses the blood-brain barrier and has a favorable pharmacokinetic profile allowing oral administration. These findings highlight the potential for optimized fast-onset antidepressants to address unmet needs in treating major depressive disorder and underscore the role of neuroplasticity modulation in drug discovery.
25C-NBOMe, a high-potency psychedelic acting on the 5-HT2A receptor, reduced cell viability in SH-SY5Y, PC12, and SN4741 cells with IC50 values of 89, 78, and 62 μM, respectively. Methamphetamine reduced viability at millimolar IC50 values in the same tests, making 25C-NBOMe over 50 times more potent than methamphetamine in reducing SH-SY5Y cell viability. 25C-NBOMe increased phosphorylated ERK expression and decreased phosphorylated Akt and phosphorylated Ser9-GSK3β. GSK3β inhibitors or MEK inhibitors prevented 25C-NBOMe-induced neurotoxicity, suggesting inhibition of the Akt pathway and activation of the ERK cascade are involved.