Current Topics in Medicinal Chemistry - Volume 6, Issue 8, 2006

The N-methyl-D-aspartate (NMDA) receptor is a major excitatory neurotransmitter receptor in the human brain and central nervous system. Over activation of this receptor as a result of a neurodegenerative event, such as cerebral ischemia or neurotrauma, has been implicated in acute disorders such as stroke. The NMDA receptor has also been linked to other progressive diseases such as Alzheimer, Parkinson, and Huntington. Thus, the quest to discover a small molecule that can regulate the NMDA receptor remains a challenging task in CNS drug discovery. This special issue of CTMC highlights the progress and recent advances in research and development involving the NMDA receptor. It is a collection of reviews authored and submitted by eminent researchers who have made significant contributions in this field. Dr. Sui Xiong Cai was personally involved in the research and discovery of ACEA-1021 a glycine/NMDA receptor antagonist and related compounds such as ACEA-1416. He provides insight into the pharmacology of these antagonists for clinical development and their potential therapeutic applications for the treatment of traumatic brain injury, pain, cocaine overdose and convulsions. Several authors focused their reviews on the subunit composition of the NMDA receptor. The NR2B subtype-selective NMDA antagonists have been an area of intense investigation in medicinal research since their discovery nearly two decades ago. The article submitted by Dr. André Schrattenholz and Vukic Soskic´ summarizes several general aspects of NMDA receptors and potential disease targets for drug development. Central to their review is the discussion on the functional regulation of NMDA receptors with respect to the NR2 subunits. Drs. István Borza and György Domány provide an account of the discovery of ifenprodil. Their review describes the design of selective NR2B antagonists using the pharmacophore of ifenprodil. On the other hand, Dr. Mark Layton, Michael Kelly and Kevin Rodzinak discuss recent efforts in the discovery and development of structurally unique NR2B subtype-selective NMDA antagonists that do not fit the classical "ifenprodil-like" pharmacophore. They provide a complete overview on the most recent developments on NR2B subtype-selective NMDA antagonists, including a comprehensive survey of the most recent literature. Professor Mingjie Zhang, Wenyu Wen and Wenning Wang discuss targeting the proteins and enzymes down stream of the NMDA receptor-signaling pathway. They specifically review the PDZ domain of PSD-95 and the critical role it plays in the NMDA receptor/neuronal nitric oxide synthase pathway. The authors provide recent results on flavonoids from Scutellaria baicalensis extracts, which bind to a pocket of the PDZ2 domain overlapping with the NR2B subunit-binding surface and provide convincing evidence that small molecules targeting the PDZ domain of PSD-95 could be a useful strategy for inhibition of glutamate-induced excitotoxicity. Professor Bernhard Wünsch and Michael Sax provide a comprehensive summary of the structure and NMDA receptor binding affinity of dexoxadrol, etoxadrol and their derivatives. The authors discuss the potential mechanism of the interactions between dexoxadrol and etoxadrol and the phencyclidine (PCP) binding site of the NMDA receptor, providing valuable insight into the development of NMDA receptor modulating compounds. Dr. Ryu Nagata and co-workers review significant contributions in the discovery of antagonists for the glycine-binding site of the NMDA receptor. In particular, they focus on the in vivo activity of antagonists from the tricyclic quinoxalinedione and indole-2-carboxylic acid series of compounds that have zwitterionic functionality. Drs. Dean Brown and Johannes Krupp provide a current assessment and comprehensive review of the potential clinical utility of NMDA antagonists for pain therapy, which is currently one of the most important and hotly contested areas in the field of the NMDA receptors. Many structurally diverse NMDA antagonists have been reported to have activity in both animal models and clinical models of neuropathic pain, although side effects have severely limited the clinical utility of these as potential therapeutics. The authors provide a current assessment of the potential clinical utility of representative examples of NMDA antagonists (i.e. glycine-site, NR2B sites and weak-binding channel blockers) that have demonstrated improved side effect profiles in animal models of pain. Dr. Craig Lindsley and co-workers describe recent progress towards validation of the NMDA receptor hypofunction........

NMDA receptors are known to be involved in nociceptive transmission and pain processing. Many structurally diverse NMDA antagonists have been reported to have activity in both animal models and clinical models of neuropathic pain. Untoward side effects such as ataxia and sedation have severely limited the clinical uses of this class of potential therapeutics. However, antagonists at the glycine-site, NR2B sites and weak-binding channel blockers have demonstrated an improved side effect profile in animal models of pain. These types of compounds may hold potential promise for future pain therapies. This review covers reported pain data surrounding representative examples of NMDA antagonists and provides a current assessment of potential clinical utility.

This article describes recent progress towards validation of the N-methyl-D-aspartate (NMDA) receptor hypofunction hypothesis of schizophrenia in preclinical models. Schizophrenia, a complex disease characterized by positive, negative and cognitive symptoms, affects 1% of the world population and requires lifelong, daily maintenance therapy. For the last several decades, thinking in this field has been dominated by the hypothesis that hyperfunction of dopamine pathways played a key role in schizophrenia. However, the therapeutic agents developed from this hypothesis have a slow onset of action and tend to improve only the positive symptoms of the disease. The NMDA receptor antagonist PCP has been shown to induce the positive, negative and cognitive symptoms of schizophrenia in healthy patients and cause a resurgence of symptoms in stable patients. These observations led to the NMDA receptor hypofunction hypothesis as an alternative theory for the underlying cause of schizophrenia. According to this hypothesis, any agent that can potentiate NMDA receptor currents has the potential to ameliorate the symptoms of schizophrenia. To date, NMDA receptor currents can be modulated by either direct action on modulatory sites on the NMDA receptor (i.e., the glycine co-agonist binding site) or indirectly by activation of G-protein coupled receptors (GPCRs) known to potentiate NMDA receptor function (i.e., mGluR5). This review will discuss the NMDA receptor hypofunction hypothesis, the NMDA receptor as an emerging target for the development of novel antipsychotic agents and progress towards in vivo target validation with GlyT1 inhibitors and mGluR5 positive allosteric modulators. Other potential targets for modulating NMDA receptor currents (polyamine sites, muscarinic receptors, etc...) will also be addressed briefly.

N-methyl-D-aspartate receptors (NMDAR) have a recognized role in neuronal plasticity while their excessive activation results in excitotoxic death. Therefore, NMDAR antagonists are considered for neuroprotective interventions. However, there is also an emerging role of NMDAR in supporting neuronal survival. Thus, during CNS development, basal NMDAR activity suppresses neuronal apoptosis while moderate NMDAR activation may, at least under some conditions, protect against excitotoxic/ischemic insults. These suggest that while protecting from excitotoxicity, NMDAR antagonists would also reduce pro-survival activity of NMDAR. Hence, the identification of the switches controlling prosurvival vs. pro-excitotoxic outcome of NMDAR stimulation may lead to development of NMDAR antagonists that selectively block the excitotoxicity while enhancing the protective NMDAR signaling. On the other hand, the existence of anti-apoptotic/pro-proliferative NMDAR signaling in transformed cells may result in new strategies to attack cancer. This review focuses on the emerging field of neuroprotective signaling mediators that are implicated in pro-survival activity of NMDAR. We discuss the evidence implicating either NR2B or nonNR2B NMDAR in mediating the protection. We also present the reports linking NMDAR-mediated protection to the activation of survival signaling kinases including ERK and Akt, or suppression of a pro-apoptotic kinase, GSK-3β. The protective role of transcription factors is also discussed. Finally, we review the existing evidence suggesting that NMDAR support survival by regulating the pro-survival trophic factor signaling and/or the cell death machinery. Although NMDAR provide a major survival input to CNS neurons, the NMDAR-activated protective signaling is poorly understood and, therefore, deserves further research effort.

Dopamine and glutamate have been shown to extensively interact in the striatum, nucleus accumbens, hippocampus and prefrontal cortex, to regulate different physiological functions, including locomotor activity, positive reinforcement, attention and working memory. Although dysfunctions of dopamine transmission have long been identified as critical determinants of neurological and neuropsychiatric disorders, such as Parkinson's disease and schizophrenia, there is now increasing evidence that concurrent alterations of dopamine and glutamate function may play a central role in the pathophysiology of these diseases. Thus, defining the characteristics of dopamine-glutamate interactions may be crucial to identify alternative molecular targets for the development of novel pharmacological tools. At the postsynaptic level, interactions between the dopamine D1 and the glutamate NMDA receptors appear to be particularly relevant. Different mechanisms are involved in this interactions: 1) D1R-dependent, second messenger-mediated phosphorylation of NMDAR subunits; 2) coordinated regulation of receptor trafficking at synaptic sites; 3) formation of an heteromeric D1/NMDA receptor complex. In this paper we review the molecular mechanisms, functional implications and pharmacological significance of D1R/NMDAR interaction via direct protein-protein oligomerization.

Glutamic acid (Glu) is the major excitatory neurotransmitter in the mammalian central nervous system (CNS) where it is involved in the physiological regulation of different processes. It has been well established that excessive endogenous Glu is associated with many acute and chronic neurodegenerative disorders such as cerebral ischemia, epilepsy, amiotrophic lateral sclerosis (ALS), Parkinson's and Alzheimer's diseases. In addition to the classical competitive glutamate receptor (GluR) antagonists, much effort has been directed toward the development of many different non-competitive antagonists of these receptors and, among them, compounds blocking the glycine site on the NMDA receptor complex (Gly/NMDA) have been widely investigated. Many Gly/NMDA receptor antagonists showed to be potential therapeutic agents in many neurological diseases such as stroke, epilepsy and neuropathic pain. Some of them, endowed also with favourable physicochemical properties and low secondary undesiderable effects, reached clinical trials.

A major neurotransmitter, L-Glutamate must be stored, transported and received, and these processes are mediated by proteins that bind this simple yet essential amino acid. Detailed evidence continues to emerge on the structure of Glu binding proteins, which includes both receptors and transporters. It appears that receptors and transporters bind to Glu in different conformations, which may present a pharmacological opportunity. This review will compare and contrast information available on Glu Receptors (AMPA, NMDA, KA and mGlu), excitatory amino acid transporters (EAATs), the system Xc- transporter (XCT) and the vesicular Glutamate transporter (GVT). The cross-reactivity of ligands which have been previously used to characterize the glutamate binding proteins with system Xc- raises some fundamental interpretational issues regarding the mechanisms through which these analogues produce CNS damage. Although at one time it was thought that unraveling selectivity among glutamate binding proteins was an intractable problem, recently the NMDA antagonist (memantine) has been approved for general medical practice for treatment of Alzheimer's disease. Two other agents are in advanced clinical trials: an Ampakine for potential improvement of cognitive disorders, and a selective mGlu agonist for treatment of anxiety. The prospects for unraveling cross-reactivity will be weighed in light of a critical comparison of the glutamate binding protein targets.