Current Drug Targets - Volume 8, Issue 5, 2007

Glutamate is the major excitatory neurotransmitter in the brain. Surprisingly, only recently have glutamate receptors become important targets for drugs designed to address a large variety of neurological and neuropsychiatric diseases. The multiplicity of glutamate receptors, both ionotropic and metabotropic, and the large variety of functions in which they are involved, have therefore provided a rich field of application for the discovery of new therapeutic approaches. In particular, glutamate receptors have been shown to play critical roles in the mechanisms underlying learning and memory, and numerous academic laboratories and pharmaceutical companies have evaluated the possibility of developing cognitive enhancers based on positive modulation of AMPA receptors. Conversely, it is also clear that AMPA receptors are implicated in epilepsy and numerous AMPA receptor antagonists are in various phases of development as anti-epileptic agents. NMDA receptors have also been the targets of drug companies. The recent approval of memantine for treatment of Azheimer's disease represents an interesting example of bench to bedside transition. On the other hand, modulators of the glycine site of the NMDA receptors as well as glycine uptake inhibitors have been shown to provide a positive complement to the traditional use of neuroleptics to manage schizophrenia. Finally, agents acting on the metabotropic glutamate receptors are also slowly making their way to the clinic. This Special Issue of Current Drug Targets will review several recent developments in both the basic sciences directed at further understand the structures and functions of the different subtypes of receptors as well as the applications of the research directed at developing new therapeutic treatments for a variety of CNS diseases. Since the cloning of the glutamate receptors in the early 90s, tremendous progress concerning the structures and functions of the different subtypes of glutamate receptors has been accomplished. This progress has led to a flurry of activities directed at the identification of molecules targeting various aspects of the receptors and receptor-related processes, i.e., modulators of the receptor themselves or of mechanisms related to transport of endogenous regulators of receptor function such as glycine, which could be useful for a variety of therapeutic indications (Fig. 1). Given the fact that glutamate is the major excitatory neurotransmitter, it is not surprising that modulating glutamate receptor functions could produce a wide range of physiological effects, and that pharmaceutical as well as biotech companies would be interested in targeting these receptors for therapeutic applications. The first contribution by Robert Oswald and colleagues focuses on the structure of the ionotropic glutamate receptors, and in particular on the role of the binding domain in receptor activation. It is now clear that ionotropic receptors have evolved from some ancestor bacterial proteins, and a lot of information is now available regarding the 3-dimensional structure of the binding domain of both AMPA and NMDA receptors. This information has also been extended to additional regulatory domains of the receptors. In particular, the N-terminal, the C-terminal domains and the interface between dimers are now better understood. Of primary importance is the elucidation of the channel activation resulting from glutamate binding to the ligand recognition domain of the receptor. Furthermore, these studies have provided important clues for the understanding of the mechanisms of action of compounds known as positive AMPA receptor modulators (PARMs) that are the subjects of the reviews by Arai and Kessler and O'Neill and Witkin. The second contribution by Arai and Kessler describes the structure and function of one particular class of PARMs, referred to as Ampakines. These molecules were derived from aniracetam and the authors discuss the evidence indicating that the various analogs that have been synthesized belong to 2 types of compounds, which appear to bind to 2 separate sites on the AMPA receptors and have slightly different physiological effects. These compounds have been shown to facilitate LTP induction and to improve learning in a variety of experimental tasks in laboratory animals as well as in humans. As also discussed in the following review, these drugs exhibit neuroprotective effects presumably through the increased expression of BDNF in various brain structures..........

Glutamate receptors mediate a vast array of processes in plants, animals and bacteria. In particular, the ionotropic glutamate receptors (iGluRs) are the most abundant excitatory neurotransmitter receptors in the mammalian central nervous system. Because these proteins are constructed from distinct folding domains, most of which can be traced to bacterial precursors, the analyses of these important receptor proteins has been performed on a variety of levels ranging from atomic structure and dynamics to behavioral studies. This review will focus on the structure and dynamics of iGluRs, with particular emphasis on the role that the glutamate-binding domain (S1S2) plays in receptor function.

Ampakines are drugs structurally derived from aniracetam that potentiate currents mediated by AMPA type glutamate receptors. These drugs slow deactivation and attenuate desensitization of AMPA receptor currents, increase synaptic responses and enhance long-term potentiation. This review focuses mainly on recent physiological studies and on evidence for two distinct subfamilies. Type I compounds like CX546 are very effective in prolonging synaptic responses while type II compounds like CX516 mainly increase response amplitude. Type I and II drugs do not compete in binding assays and thus presumably act through separate sites. Their differences are likely to have consequences also for synaptic plasticity and behavior. Thus, while all ampakines facilitated long-term potentiation, only CX546 enhanced long-term depression. Further discussed are studies showing that ampakine effects vary substantially between neurons, with increases in EPSCs being larger in CA1 pyramidal cells than in thalamus and in hippocampal interneurons. In behavioral tests, ampakines facilitate learning in many paradigms including odor discrimination, spatial mazes, and conditioning, and they improved short-term memory in a non-matching-to-sample task. Positive results were also obtained in various psychological tests with human subjects. The drugs were effective in correcting behaviors in various animal models of schizophrenia and depression. Lastly, evidence is discussed that ampakines have few adverse effects at therapeutically relevant concentrations and that they protect neurons against neurotoxic insults, in part by mobilizing growth factors like BDNF. Type II drugs like CX516 in particular appear to be inherently safe since their ability to prolong responses is kinetically limited.

α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors mediate most of the excitatory neurotransmission and play a key role in synaptic plasticity in the mammalian central nervous system (CNS). In recent years several classes of AMPA receptor potentiators have been reported in the literature, including pyrrolidones (piracetam, aniracetam), benzothiazides (cyclothiazide), benzylpiperidines (CX-516, CX-546) and biarylpropylsulfonamides (LY392098, LY404187, LY450108, LY451395 and LY503430). Clinical and preclinical data have suggested that positive modulation of AMPA receptors may be therapeutically effective in the treatment of cognitive deficits. However, recent evidence has shown that in addition to modulating fast synaptic plasticity and memory processes, AMPA receptor potentiators alter downstream signalling pathways and may thereby have utility in other CNS disorders. The present review summarises studies into the effects of AMPA receptor potentiators (with a focus on the biarylpropylsulfonamides) in rodent models of depression and Parkinson's disease.

Alzheimer's disease (AD) and Vascular dementia represent the most common forms of dementia. If left unabated, the economic cost of caring for patients with these maladies would consume the entire gross national product of the industrialized world by the middle of this century. Until recently, the only available drugs for this condition were cholinergic treatments, which symptomatically enhance cognitive state to some degree, but they were not neuroprotective. Many potential neuroprotective drugs tested in clinical trials failed because of intolerable side effects. However, after our discovery of its clinically-tolerated mechanism of action, one putatively neuroprotective drug, memantine, was recently approved by the European Union and the U.S. Food and Drug Administration (FDA) for the treatment of dementia. Recent phase 3 clinical trials have shown that memantine is effective in the treatment of both mild and moderate-to-severe Alzheimer's disease and possibly Vascular dementia (multi-infarct dementia). Here we review the molecular mechanism of memantine's action and also the basis for the drug's use in these neurological diseases, which are mediated at least in part by excitotoxicity. Excitotoxicity is defined as excessive exposure to the neurotransmitter glutamate or overstimulation of its membrane receptors, leading to neuronal injury or death. Excitotoxic neuronal cell damage is mediated in part by overactivation of N-methyl-D-aspartate (NMDA)-type glutamate receptors, which results in excessive Ca2+ influx through the receptor associated ion channel and subsequent free radical formation. Physiological NMDA receptor activity, however, is also essential for normal neuronal function. This means that potential neuroprotective agents that block virtually all NMDA receptor activity will very likely have unacceptable clinical side effects. For this reason many previous NMDA receptor antagonists have disappointingly failed advanced clinical trials for a number of neurodegenerative disorders. In contrast, studies in our laboratory have shown that the adamantane derivative, memantine, preferentially blocks excessive NMDA receptor activity without disrupting normal activity. Memantine does this through its action as an uncompetitive, low-affinity, open-channel blocker; it enters the receptor-associated ion channel preferentially when it is excessively open, and, most importantly, its off-rate is relatively fast so that it does not substantially accumulate in the channel to interfere with subsequent normal synaptic transmission. Clinical use has corroborated the prediction that memantine is well tolerated. Besides Alzheimer's disease, memantine is currently in trials for additional neurological disorders, including HIVassociated dementia, depression, glaucoma, and severe neuropathic pain. A series of second-generation memantine derivatives are currently in development and may prove to have even greater neuroprotective properties than memantine. These second-generation drugs take advantage of the fact that the NMDA receptor has other modulatory sites in addition to its ion channel that potentially could also be used for safe but effective clinical intervention.

The N-methyl-D-aspartate receptor (NMDAR), a subtype of ionotropic glutamate receptor, has been implicated in a host of chronic and acute neurological disorders. Accordingly, much emphasis has been placed on the development of safe and effective therapeutic agents that specifically antagonize this target. The conantokins are a class of small, naturally occurring peptides that inhibit ion flow through the NMDAR. Some conantokins demonstrate receptor subunit selectivity, a pharmacological attribute of emerging importance in the search for suitable drug candidates. The current review summarizes the NMDAR inhibitory properties of the conantokins, including structure-function relationships and mechanism of action. This information is fundamental to the rational design of suitable agents that can effectively treat pathophysiologies linked to NMDAR dysfunction.

In the central nervous system, glutamate is essential for a proper synaptic communication in neuronal networks supporting critical behavioral activities such as learning and memory. Dysfunction of glutamatergic excitatory neurotransmission has been implicated in numerous neurological and pyschiatric disorders and a growing body of research suggests that potentiation of NMDA receptor function may represent a novel approach for the treatment of schizophrenia. An actively pursued strategy to potentiate NMDA receptor function is to increase synaptic levels of the neurotransmitter glycine by blocking the glycine transporter type 1 (GlyT1). Since glycine acts as a co-agonist at the NMDA receptor, this approach could enhance the effectiveness of normal NMDA receptor-mediated glutamatergic neurotransmission. Recent research on the physiology of this uptake system as well as on the development and preclinical testing of novel GlyT1 inhibitors have greatly enhanced our knowledge of the role of this transporter in the modulation of NMDA receptor activity and suggested that this approach may be feasible. Clinical studies with novel glycine reuptake inhibitors will provide critical information regarding the validity of this therapeutic concept for the treatment of schizophrenia and other disorders associated with NMDA receptor hypofunction.

L-glutamate (Glu), the main excitatory amino acid neurotransmitter in the mammalian central nervous system, is involved in many physiological functions, including learning and memory, but also in toxic phenomena occurring in numerous degenerative or neurological diseases. These functions mainly result from its interaction with Glu receptors (GluRs). The broad spectrum of roles played by glutamate derived from the large number of membrane receptors, which are currently classified in two main categories, ionotropic (iGluRs) and metabotropic (mGluRs) receptors. The iGluRs are ion channels, permeant to Na+ (Ca2+) while the mGluRs belongs to the superfamily of G-protein coupled receptors (GPCRs). Despite continuous efforts over more than two decades, the use of iGluR agonists or antagonists to improve or inhibit excitatory transmission in pathological states still remains a major challenge, though the discovery and development of recent molecules may prove it worthwhile. This probably results form the vital role of fast excitatory transmission in many fundamental physiological functions. Since the discovery of mGluRs, hope has emerged. Indeed, mGluRs are mainly involved in the regulation of fast excitatory transmission. Consequently, it was logically thought that modulating mGluRs with agonists or antagonists might lead to more subtle regulation of fast excitatory transmission than by directly blocking iGluRs. As a result of intensive investigation, new drugs permitting to discriminate between these receptors have emerged. Moreover, a new class of molecules acting as negative or positive allosteric modulators or mGluRs is now available and appears to be promising. In the following, we will review the classification of mGluRs and the functions in which mGluRs are involved. We will focus on their potential as therapeutic targets for improving numerous physiological functions and for different neurodegenerative and neuropsychiatric disorders, which are related to malfunction of Glu signaling in human beings.