Discovery of a Novel Orally Active Ketamine Derivative with Dual Analgesic and Antidepressant Activities, Lacking Psychomimetic Effects

This study investigated the synthesis, characterization, and in silico analysis of novel N-acetamide ketamine derivatives aimed at evaluating their analgesic, anesthetic, and antidepressant properties. The synthesis commenced with the preparation of chloroacetylamide derivatives, which were subsequently reacted with ketamine hydrochloride, yielding 16 derivatives k₁ to k₁₆. These compounds were characterized through H¹ NMR, C¹³ NMR, mass spectroscopy (EIMS), and elemental analysis, followed by an assessment of their physicochemical properties. The analgesic efficacy of all of the synthesized derivatives was evaluated using the acetic acid-induced writhing test via intraperitoneal administration. The best-performing molecule was further evaluated for analgesic (acetic acid-induced writhing test, tail suspension test (TST), and hot plate test) and anti-inflammatory (carrageenan-induced paw edema) activities. For antidepressant effects, all derivatives were compared with ketamine in a lipopolysaccharide-induced model of depression in mice through the forced swimming test, open field test (OFT), sucrose preference test (SPT), and TST. It was observed that among all the derivatives, molecule k₁ demonstrated comparable analgesic activity to ketamine. Further, compound k₁ also exhibited the highest antidepressant potential during the forced swimming test, OFT, SPT, and TST. k₁ was further compared with ketamine for their activities intraperitoneally and orally where k₁ exhibited comparable antidepressant effects to ketamine. Henceforth, the psychomimetic potential of k₁ was evaluated through loss of righting reflex and Y-maze tests. Very interestingly, these tests indicated approximately no psychomimetic activity of k₁ compared to ketamine intraperitoneally and orally. Finally, molecular docking studies were conducted targeting the NMDA receptor at the JC09 ketamine binding pocket (PDB ID: 7EU7), where all synthesized derivatives exhibited significant binding affinities relative to ketamine. These findings suggest that the newly synthesized N-acetamide ketamine derivative k₁ possesses promising pharmacological profiles, warranting further exploration.