Novel NMDA receptor modulators: an update

Abstract

Summary Introduction The NMDA receptor is a ligand-gated ion channel that plays a critical role in higher level brain processes and has been implicated in a range of neurological and psychiatric conditions. Although initial studies for the use of NMDA receptor antagonists in neuroprotection were unsuccessful, more recently, NMDA receptor antagonists have shown clinical promise in other indications such as Alzheimer’s disease, Parkinson’s disease, pain and depression. Based on the clinical observations and more recent insights into receptor pharmacology, new modulatory approaches are beginning to emerge, with potential therapeutic benefit. Areas Covered The article covers the known pharmacology and important features regarding NMDA receptors and their function. A discussion of pre-clinical and clinical relevance is included, as well. The subsequent patent literature review highlights the current state of the art targeting the receptor since the last review in 2010. Expert Opinion The complex nature of the NMDA receptor structure and function is becoming better understood. As knowledge about this receptor increases, it opens up new opportunities for targeting the receptor for many therapeutic indications. New strategies and advances in older technologies will need to be further developed before clinical success can be achieved. First-in-class potentiators and subunit-selective agents form the basis for most new strategies, complemented by efforts to limit off-target liability and fine-tune on-target properties.

Tryptophanol-derived oxazolopiperidone lactams: Identification of a hit compound as NMDA receptor antagonist

“…In the last decades, several types of NMDAR antagonists with a wide range of action mechanisms have been reported but unfortunately only few exhibited proper pharmacokinetics and tolerable side effects in human trials. 6 A successful example is amantadine, a low-affinity NMDA channel blocker, currently used to mitigate levodopa-induced dyskinesia in Parkinson's disease. 7 In 2009, a group of oxazolidines 1 was described as NMDAR antagonists by preventing the binding of NMDAR ligands through a yet unknown mechanism of action.…”

Excitotoxicity: An Organized Crime at The Cellular Level

“…Nevertheless, its effect size appears to be reduced [106], and it significantly increases the risk for side effects such as somnolence, weight gain, hypertension, falls and various nervous system disorders [107]. Thus, the search for further NMDAR antagonists with improved clinical utility or tolerability remains subject to intense ongoing research [108].…”

Current and Future Issues in the development of spinal agents for the management of pain

“…ii) The NMDA ionophore is constituted of a variety of subunits. Ionophores constituted of different subunits have different binding profiles and are differentially distributed [200,201]. One such subtype is the NR2B subunit.…”

“…Specific antagonists such as Ifenprodil [202], Ro 25-6981 [202,203] and Conantokin G [204] has antihyperpathic effects in models of spinal injury and facilitated processing. Other NMDA ionophore-associated targets for which ligands have been shown to produce analgesia include the glycine binding site and the polyamine binding site [201,205]; iii) Magnesium sulphate is a noncompetitive antagonist of the Nmethyl-d-aspartate (NMDA) receptor and thus can modify nociceptive modulation [206][207]. Limited preclinical safety studies have been performed examine the effects of bolus delivery in several species.…”