Novel MOA: REL-1017 works as an NMDAR channel blocker with preferential selectivity for hyperactive channels.

REL-1017 is a novel N-methyl-D-aspartate receptor (NMDAR) antagonist being investigated as an adjunctive treatment for MDD via pathways that are markedly different from most currently approved drugs.

REL-1017 has been shown to preferentially block hyperactive NMDA-receptor (NMDAR) channels. These channels are situated in the membrane of neurons and receive signals via glutamate, a neurotransmitter. NMDA stands for N-methyl-D-aspartate, a chemical able to open the channel, in a mechanism similar to that of neurotransmitter glutamate.

NMDARs are known to have a role in depression, as well as in normal physiological functions. Blocking hyperactive NMDAR channels represents a novel approach to treating depression with a mechanism that is different from the classes of currently approved drugs.

REL-1017 works as an NMDA receptor (NMDAR) channel blocker that preferentially targets hyperactive channels. More specifically, REL-1017 shows preferential blocking of NMDAR subtypes that may be of particular importance in major depressive disorder (MDD), while avoiding effects on those channels that are associated with normal physiological functions. With this mechanism, REL-1017 is being evaluated to determine whether it can provide the benefits associated with NMDAR channel block without psychotomimetic effects or other cognitive side effects associated with other drugs that work on the same receptors.

REL-1017 is the dextro-(or right side)-isomer of its parent molecule, racemic methadone. As described by the US Drug Enforcement Agency (DEA), the opioid effects of racemic methadone are due to its levo-isomer, while the dextro-isomer lacks significant respiratory depressant action and addiction liability¹. In addition to blocking hyperactive open NMDAR channels, REL-1017 has been shown to increase plasma levels of BDNF and potentially induce neural plasticity.

Relmada has built a strong intellectual property position around REL-1017, with key patent protections extending into the mid-2030s.

1) DEA, Drug and Chemical Evaluation Section, Methadone, July 2019.

2) Fogaça MV, Fukumoto K, Franklin T, et al. N-Methyl-D-aspartate receptor antagonist d-methadone produces rapid, mTORC1-dependent antidepressant effects. Neuropsychopharmacology. 2019;44(13):2230–2238.

3) Results from REL-1017 phase 2 trial in MDD

4) De Martin S, Vitolo O, Bernstein G, Alimonti A, et al. The NMDAR Antagonist Dextromethadone Increases Plasma BDNF Levels in Healthy Volunteers Undergoing a 14-Day In-Patient Phase 1 Study. ACNP 57th Annual Meeting: Poster Session II. Neuropsychopharmacol. 43, 228–382 (2018).

Novel MOA: REL-1017 works as an NMDAR channel blocker with preferential selectivity for hyperactive channels.

REL-1017 is thought to work through a selective, preferential block of hyperactive channels associated with MDD.

REL-1017 preferentially targets hyperactive NMDAR channels.