Demystifying the Antidepressant Mechanism of Action of Stinels, a Novel Class of Neuroplastogens: Positive Allosteric Modulators of the NMDA Receptor.
Pharmaceuticals (Basel, Switzerland) January 24, 2025 John E Donello, Roger S McIntyre, Donald B Pickel et al. 14 citations
Plastogens are a class of therapeutics that rapidly promote changes in neuroplasticity. Ketamine, a notable example, is an N-methyl-D-aspartate receptor (NMDAR) antagonist with rapid and long-term antidepressant effects but also psychotomimetic and dissociative side effects. Stinels—rapastinel, apimostinel, and zelquistinel—are plastogens with improved safety and tolerability profiles. This review clarifies the mechanism of stinels, defining them as positive allosteric modulators of NMDAR activity with a novel regulatory binding site, contrasting with earlier descriptions of glycine-like partial agonists. The review presents the rationale for targeting NMDARs in treatment-resistant depression and other psychiatric conditions.