|Synonyms||NRX-1074; AGN-241660; Threonyl-prolyl-2R-(2-benzyl)-prolyl-threonine amide|
|Chemical and physical data|
|Molar mass||503.600 g·mol−1|
|3D model (JSmol)|
Apimostinel (former developmental code name NRX-1074) is an antidepressant, acting as a selective partial agonist of an allosteric site of the glycine site of the NMDA receptor complex, which is under investigation by Naurex and Allergan for the treatment of major depressive disorder (MDD). As of 2015, an intravenous formulation of apimostinel is in a phase II clinical trial for MDD, and an oral formulation is concurrently in phase I trials for MDD.
Its mechanism of action and effects are similar to those of rapastinel (GLYX-13), which is under development as an adjunctive therapy for treatment-resistant depression also by Naurex. However, apimostinel is 100-fold more potent by weight and, whereas rapastinel must be administered via intravenous injection, is orally-active. Apimostinel is intended by Naurex as an improved, follow-up drug to rapastinel. Similarly to rapastinel, apimostinel is an amidated tetrapeptide, and has almost an identical chemical structure to rapastinel, but has been structurally modified via the addition of a benzyl group. The drug has shown rapid antidepressant effects in pre-clinical models of depression. In addition, similarly to rapastinel, it is well-tolerated and lacks the schizophrenia-like psychotomimetic effects of other NMDA receptor antagonists such as ketamine.
Despite the mounting evidence indicating that ketamine has rapid and robust antidepressant properties (and notwithstanding the earlier mentioned preliminary clinical data indicating that long-term, low-dose ketamine may be both tolerable and effective; e.g., Messer et al., 2010), concerns over ketamine’s psychotomimetic effects have spurred intensive efforts to develop safer and more tolerable glutamate-based antidepressants. At the vanguard of this movement are the “next generation” NMDA receptor antagonists. Included here are the aminoadamantanes, memantine and amantadine (Sani et al., 2012); the NR2B-selective antagonists, traxoprodil (CP-101,606; Preskorn et al., 2008) and MK-0657 (Ibrahim et al., 2012a); and the low-affinity NMDA channel blocker AZD6765 (Zarate et al., 2013). The NMDA receptor glycine-site functional partial agonist, GLYX-13, and its orally bioavailable and presumed more potent analog, NRX-1074, have also garnered the recent attention of researchers and clinicians (Burgdorf et al., 2013; Dolgin, 2013), as have several modulators of metabotropic glutamate receptors (e.g., the mGluR7 allosteric agonist AMN082; Bradley et al., 2012) and select α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor potentiators (e.g., Org 26576; Nations et al., 2012).