Unlocking the Therapeutic Potential of the NMDA Receptor
by Joseph R. Moskal, PhD, President and CSO; J. David Leander, PhD, Chief Scientific Advisor; and Ronald M. Burch, MD, PhD, CMO, Naurex, Inc., Evanston, Ill.
The glutamate receptor subtype known as N-methyl-D-aspartic acid (NMDA) plays a central role in modulating aspects of brain activity. Naurex is developing a pipeline of small peptides and synthetic small molecules that modulate the NMDA receptor (NMDAR) at the glycine site. Naurex’s lead compound is GLYX-13, a novel glycine-site functional partial agonist (GFPA) selective NMDAR modulator that is in clinical development for the treatment of depression.
Pharmaceutical firms have been developing NMDAR modulators for decades, and a few, including ketamine and memantine, are marketed for non-depression indications. Known NMDAR antagonists rapidly reduce depression scores in patients with treatment-resistant depression and result in remission in up to a third of patients.1,2 A recent article in Science identified activation of various signaling pathway proteins underlying the speed and efficacy of NMDAR modulators, providing valuable insight into the mechanism of action of these drugs.3,4 These studies have confirmed the NMDA receptor as a high-interest target in depression. Despite strong efficacy and speed of onset, classic NMDAR blockers are associated with significant toxicities at or near their therapeutic doses, including dissociative effects such as hallucinations, as well as sedation and abuse liability.5,6 Until now, the narrow margin between therapeutic and adverse effects has limited the use of these agents.
Naurex’s GFPAs have been designed to achieve the efficacy of classic NMDAR modulators without their limiting side effects. In a Phase 1 trial of GLYX-13, the incidence of adverse events among subjects receiving GLYX-13 and placebo was similar. There were no serious adverse events and no signs of dissociative side effects, even at doses of GLYX-13 significantly higher than the expected therapeutic dose. In preclinical studies, GLYX-13 demonstrated promising signs of robust antidepressant activity with excellent safety, achieving a therapeutic index of 500 or more—an unprecedented result for drugs targeting the NMDAR. These studies also showed that GLYX-13 had an immediate onset of antidepressant effect—within 20 minutes of administering a single dose—that was sustained for at least two weeks.7 Naurex plans to initiate a Phase 2 trial this year to evaluate GLYX-13 in patients who are not achieving an adequate response to their current antidepressant agent.
Naurex’s NRX-1050 series of novel GFPA agents is in preclinical development. Slight variations in the structures of these orally available small molecules may enable them to modulate specific NMDAR subtypes associated with different diseases. These compounds may have broad CNS potential, with demonstrated activity in models of depression, anxiety, neuropathic pain, and learning and cognition.
1. Zarate CA Jr, et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006; 63(8):856-64.
2. Preskorn SH, et al. An innovative design to establish proof of concept of the antidepressant effects of the NR2B subunit selective N-methyl-D-aspartate antagonist, CP-101,606, in patients with treatment-refractory major depressive disorder. J Clin Psychopharmacol. 2008; 28(6):631-7.
3. Li N, et al. mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists. Science. 2010; 329(5994):959-62.
4. Cryan JF, O’Learty OF, A Glutamate Pathway to Faster-Acting Antidepressants? Science. 2010; 329(5994):913-4.
5. Skolnick P, Popik P, Trullas R. Glutamate-based antidepressants: 20 years on.Trends Pharmacol Sci. 2009; 30(11):563-9.
6. Machado-Vieira R, Salvadore G, Luckenbaugh DA, Manji HK, Zarate CA Jr. Rapid onset of antidepressant action: a new paradigm in the research and treatment of major depressive disorder. J Clin Psychiatry. 2008; 69(6):946-58.
7. Moskal J, Burgdorf J. Northwestern University, Evanston, IL, The anti-depressant and anxiolytic properties of GLYX-13: a Glycine-site Functional Partial Agonist (GFPA), a novel mechanism for modulating NMDA receptors. Presented at the 2009 Annual Meeting of the American College of Neuropsychopharmacology.