Demystifying the Antidepressant Mechanism of Action of Stinels, a Novel Class of Neuroplastogens: Positive Allosteric Modulators of the NMDA Receptor

Plastogens are a class of therapeutics that function by rapidly promoting changes in neuroplasticity. A notable example, ketamine, is receiving great attention due to its combined rapid and long-term antidepressant effects. Ketamine is an N-methyl-D-aspartate receptor (NMDAR) antagonist, and, in addition to its therapeutic activity, it is associated with psychotomimetic and dissociative side effects. Stinels—rapastinel, apimostinel, and zelquistinel—are also plastogens not only with rapid and long-term antidepressant effects but also with improved safety and tolerability profiles compared to ketamine. Previous descriptions of the mechanism by which stinels modulate NMDAR activity have been inconsistent and, at times, contradictory. The purpose of this review is to clarify the mechanism of action and contextualize stinels within a broader class of NMDAR-targeting therapeutics. In this review, we present the rationale behind targeting NMDARs for treatment-resistant depression and other psychiatric conditions, describe the various mechanisms by which NMDAR activity is regulated by different classes of therapeutics, and present evidence for the stinel mechanism. In contrast with previous descriptions of glycine-like NMDAR partial agonists, we define stinels as positive allosteric modulators of NMDAR activity with a novel regulatory binding site.