Current Topics in Medicinal Chemistry - Volume 6, Issue 7, 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. 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...........

Glutamate is the main excitatory neurotransmitter in central nervous system (CNS) and NMDA receptors are one of the major classes of ionotropic glutamate receptors. NMDA receptors have been known to play critical roles in normal CNS activities, as well as in many pathological conditions, including both acute and chronic diseases. The discovery of glycine as a coagonist of NMDA receptors has led to intensive research of glycine/NMDA antagonists as potential CNS drugs. The robust efficacy of glycine/NMDA antagonists, such as ACEA-1021 (5), in animal model of brain ischemia, together with good safety profile in animal models and in clinical trials, suggested that this class of NMDA antagonists should have good chance of success in the clinic as neuroprotectants. The clinical trial of ACEA-1021 for stroke was discontinued, mainly due to low solubility and lack of metabolism of the drug that led to the observation of crystals in the urine of some of the patients. However, through SAR studies, compounds such as ACEA-1416 (10) have been identified with improved properties, such as higher in vivo potency and site for potential metabolism. Therefore these compounds should be able to overcome some of the liabilities of ACEA-1021 and potentially could be developed as neuroprotectants. Based on the preclinical and clinical studies of glycine/NMDA antagonists, as well as the clinical experiences with t-PA, initiation of treatment within a short time window after the onset of stroke could be critical for the success of these antagonists in clinical trials. This can be accomplished by implementing the procedure developed for t- PA clinical trials, with modification based on the safety profile of glycine/NMDA antagonists, for future clinical trial to administer the drug as soon as possible after stroke onset. In addition, glycine/NMDA antagonists also have other potential therapeutic applications, such as for the treatment of traumatic brain injury, pain, cocaine overdose and convulsions.

Glutamate receptors of the N-methyl-D-asparate (NMDA-) subtype are tetrameric allosteric and ligand-gated calcium channels. They are modulated by a variety of endogenous ligands and ions and play a pivotal role in memoryrelated signal transduction due to a voltage-dependent block by magnesium, which makes them Hebbian coincidence detectors. On the structural level NMDA receptors have an enormous flexibility due to seven genes (NR1, NR2A-D and NR3A-B), alternative splicing, RNA-editing and extensive posttranslational modifications, like phosphorylation and glycosylation. NMDA receptors are thought to be responsible for excitotoxicity and subsequent downstream events like neuroinflammation and apoptosis and thus have been implicated in many important human pathologies, ranging from amyotrophic lateral sclerosis, Alzheimer's and Parkinson' disease, depression, epilepsy, trauma and stroke to schizophrenia. This fundamental significance of NMDA receptor-related excitotoxicity is discussed in the context of the developing clinical success of Memantine, but moreover set into relation to various proteomic and genetic markers of said diseases. The very complex localisational and functional regulation of NMDA receptors appears to be dependent on neuregulins and receptor tyrosine kinases in cholesterol-rich membrane domains (lipid rafts), calcium-related mitochondrial feedback-loops and subsynaptic structural elements like PSD-95 (post-synaptic density protein of 95 kD). The flexibility and multitude of interaction partners and possibilities of these highly dynamic molecular systems are discussed in terms of drug development strategies, in particular comparing high affinity and sub-type specific ligands to currently successful or promising therapies.

The quest for NR2B subtype selective NMDA antagonists started almost twenty years ago. The structure of ifenprodil, the prototype of this group of compounds, inspired many medicinal chemists in several research units. Different approaches led to the identification of the pharmacophore and several distinct classes of compounds containing this pharmacophore. From these studies a few drug candidates emerged and clinical trials proved the viability of the concept. This article attempted to follow the evolution from ifenprodil, a multiple ligand, to selective NR2B antagonists.

Over activation of the NMDA receptor complex has been implicated in a number of neurological conditions. The use of NMDA antagonists as therapeutic agents has been limited by serious cognitive and motor side effects. Significant efforts have been reported in the development of NR2B subtype-selective antagonists, which have shown efficacy without the side effects observed with nonspecific NMDA antagonists. Classical ifenprodil-like molecules containing benzyl- and phenylpiperidines attached to a phenol or an appropriate isostere by a linker have provided valuable chemical leads as potential therapeutic agents. In this review, recent efforts in the discovery and development of structurally unique NR2B subtype-selective NMDA antagonists that do not fit the classical "ifenprodil-like" pharmacophore will be discussed.

N-methyl-D-aspartate (NMDA) receptors play essential roles in the normal physiology of neurons, and these receptors are also largely responsible for glutamate-induced excitotoxicity. Since treatments of glutamate-induced excitotoxicity by NMDA receptor inhibitors often result in adverse side effects, alternative treatment approaches have been actively sought in recent years. One potential approach is to target proteins and enzymes down stream of the NMDA receptor signaling pathways. Extensive studies in recent years have demonstrated that PDZ domains of PSD-95 play critical roles in scaffolding the NMDA receptor/neuronal nitric oxide synthase pathway. Therefore, PSD-95 PDZ domains become attractive targets for treatment of glutamate-induced overproduction of nitric oxide. The strategy is to develop small compounds that can effectively block protein-protein interactions mediated by the PDZ domains of PSD-95. Biochemical and structural studies of PDZ/target interactions have indicated that developing small molecules to compete with PDZ targets is a feasible approach. We provide an example demonstrating the discovery and further development of small molecules capable of disrupting PSD-95/NMDA receptor and/or PSD-95/neuronal nitric oxide synthase complexes.

In the mid 1960s the (dioxolan-4-yl)piperidine derivatives dexoxadrol ((S,S)-1a) and etoxadrol ((S,S,S)-2a) were synthesized. Their pharmacological potential as analgesics, anesthetics and local anesthetics was evaluated in animal models and later on in clinical trials with patients. However, severe side effects including psychotomimetic effects, unpleasant dreams and aberrations stopped the clinical evaluation of dexoxadrol and etoxadrol. Both dioxolane derivatives represent NMDA receptor antagonists, which possess high affinity to the phencyclidine binding site within the NMDA receptor associated ion channel. In this review relationships between the structure of acetalic dexoxadrol analogues and homologues and their affinity toward the phencyclidine binding site of the NMDA receptor are summarized. In particular, high affinity is attained with compounds bearing two phenyl residues or one phenyl residue and an alkyl residue with two or three carbon atoms at the acetalic center. At least one oxygen atom of the oxygen heterocycle is necessary. Instead of the entire piperidine ring aminoalkyl substructures are sufficient for strong receptor interactions. Compounds with a primary amino moiety generally display the highest receptor affinity, whereas tertiary amines possess low affinity. Enlargement of the 1,3-dioxolane ring to a 1,3-dioxane ring or elongation of the oxygen heterocycle / amino group distance results in compounds with considerable NMDA receptor affinity.

This review article describes the development of in vivo active antagonists for the glycine binding site of the NMethyl- D-Aspartate (NMDA) receptor. There were several difficulties in identifying a class of antagonists with in vivo efficacy and only a few compounds succeeded in emerging with activity in vivo. A series of tricyclic quinoxalinediones was highly potent glycine antagonists in vitro and the derivatives having a zwitterionic moiety including SM-18400 indeed showed in vivo activity. Similarly, tricyclic indole-2-carboxylic acids having a zwitterionic moiety such as SM- 31900 were also active in vivo. In fact, SM-18400 and SM-31900 exhibited efficacy in several animal stroke models using intravenous infusion protocols. The practical syntheses of SM-18400 and SM-31900 as well as the novel synthesis of moderately active glycine antagonists, tricyclic azakynurenic acids, were also developed.