Discovery of a Novel Orally Active Ketamine Derivative with Dual Analgesic and Antidepressant Activities, Lacking Psychomimetic Effects.
ACS chemical neuroscience March 5, 2025 Syed Muzzammil Masaud, Humaira Nadeem, Babar Murtaza et al. 3 citations
Sixteen novel N-acetamide ketamine derivatives (k1 to k16) were synthesized and characterized. In mouse models, derivative k1 showed analgesic activity comparable to ketamine and the highest antidepressant potential among all derivatives, performing similarly to ketamine in forced swimming, open field, sucrose preference, and tail suspension tests. Notably, k1 exhibited almost no psychomimetic activity—assessed via loss of righting reflex and Y-maze tests—unlike ketamine. Molecular docking against the NMDA receptor (PDB ID: 7EU7) indicated all derivatives had significant binding affinities relative to ketamine. These results suggest k1 has a promising pharmacological profile with reduced psychomimetic side effects.