Editorial [Hot Topic: NMDA Receptors as Targets in Medicinal Chemistry (Guest Editor: Dr. William Metz)]

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. Andre 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. Istvn Borza and Gyorgy Domany 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 hypothesis of schizophrenia in preclinical models. Historically, treatment for schizophrenic patients has centered on D2 dopamine receptor antagonists...........