Editorial [Hot Topic: Glutamate Receptors and Related Processes as Drug Targets (Guest Editor: Michel Baudry)]

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..........