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R&D
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NMDA Receptor Modulators as Potential CNS Drugs
The glutamate receptor subtype known as N-methyl-D-aspartic acid (NMDA) plays a central role in modulating aspects of brain activity in the central nervous system, such as synaptic transmission, synaptic plasticity and excitotoxicity. Major pharmaceutical firms have been developing NMDA receptor modulators for over 20 years, and a few, including Memantine®, ketamine, D-cycloserine and dextromethorphan are marketed for other indications, generating annual sales of more than $1 billion.
The antidepressant potential of modulating the NMDA receptor has been confirmed by data from clinical studies with known NMDA receptor antagonists, which produced significant reductions in depression scores in patients with treatment-resistant depression. These data have confirmed the NMDA receptor as a novel target of high interest in depression – representing a potentially entirely new way to treat patients who do not respond to current therapies. But while the efficacy of these drugs is promising, they are also associated with significant toxicities at doses that are very close to the therapeutic dose. These side effects include dissociative effects, sedation, and abuse and addiction potential. Until now, the narrow margin between therapeutic effects and adverse effects has limited the full therapeutic potential of these agents.
A Novel Approach: Glycine Site Functional Partial Agonists
Naurex scientists designed its novel NMDA receptor Glycine Site Functional Partial Agonists (GFPAs) to achieve the efficacy of NMDA modulators without these limiting side effects. In preclinical studies to date, Naurex’s GFPA modulators have demonstrated the therapeutic efficacy of classic NMDA receptor modulators without their limiting side effects.
Preclinical data from lead program GLYX-13 presented at a recent major medical meeting showed that it demonstrated:
- Robust antidepressant-like and anxiolytic-like activity with no signs of CNS-related side effects, achieving a therapeutic index of 500 or more, an unprecedented result for drugs targeting the NMDA receptor.
The preclinical studies also showed that GLYX-13:
- Has a rapid onset--the antidepressant effects of GLYX-13 were evident within 20 minutes of administering a single dose
- Affects both the positive and negative symptoms of depression
- Is long-acting—demonstrating an antidepressant-like effect lasting more than 96-hours after a single dose.
Naurex is also developing the NRX-1050 series of GFPA modulators — a second generation structurally distinct, orally available series. It includes multiple potential lead molecules and in vivo proof-of-concept data have been generated.
GLYX-13 Clinical Trials
The GLYX-13 Phase I trial is a randomized, double-blind, placebo-controlled single ascending dose level study of the safety, tolerability and pharmacokinetics of GLYX-13. The trial is currently recruiting and plans to enroll 20 healthy volunteers. The primary outcome measure is observed and laboratory-confirmed safety. Drug pharmacokinetics will also be measured.
For more information about the GLYX-13 Phase I trial, see www.clinicaltrials.gov.
