The novel methoxetamine analogs N-ethylnorketamine hydrochloride (NENK), 2-MeO-N-ethylketamine hydrochloride (2-MeO-NEK), and 4-MeO-N-ethylketamine hydrochloride (4-MeO-NEK) elicit rapid antidepressant effects via activation of AMPA and 5-HT2 receptors
Psychopharmacology March 19, 2019 L. Sayson, Chrislean Jun Botanas, Raly James Perez Custodio et al.
Three novel analogs of methoxetamine (MXE), an NMDA receptor antagonist related to ketamine, showed antidepressant-like effects in mice. The compounds—NENK, 2-MeO-NEK, and 4-MeO-NEK—reduced immobility time in the forced swimming and tail suspension tests, indicating reduced behavioral despair. Their effects were blocked by an AMPA receptor antagonist (NBQX) and a 5-HT2 receptor antagonist (ketanserin), suggesting involvement of both glutamatergic and serotonergic systems. The analogs also altered mRNA levels of AMPA receptor subunits and brain-derived neurotrophic factor in the hippocampus and prefrontal cortex. These findings suggest the compounds may offer rapid antidepressant effects, though further research is needed.