commonly used AMPAR antagonists are the quinoxaline-diones (such as DNQX and CNQX), which are potent non-NMDA antagonists with selectivity for AMPAR (20-fold) over KARs. Tezampanel is a competitive AMPA/GluK1 antagonist with increased potency, and its orally active prodrug NGX426 is the first AMPA/KAR antagonist to be studied in clinical trials for chronic pain, including migraine and neurophatic pain. Some derivatives of tezampa-nel are functioning as selective KAR GluK1 antagonists (LY382884 and LY466195). Selectivity for AMPAR over GluK1 was only achieved when developing noncompetitive antagonists, e.g., GYKI-53784 and CP-456,022. These AMPAR antagonists do not function as open-channel blockers but are instead binding in the linker regions between the extracellular and TM domains, affecting the con-formational changes induced by the agonist. Another potent and highly selective, noncompetitive, AMPAR antagonist Perampanel was initially developed as an add-on therapy to L-Dopa in Parkinson's disease, but is presently under investigation for neuropathic pain and epilepsy. UBP203 and UBP316 are potent competitive antagonists with enhanced KAR GluK1 selectivity achieved by SAR studies of the natural product willardiine. Selective competitive antagonists for the other KAR subtypes are not yet available. Noncompetitive antagonists have so far been identified for the GluK1 and GluK2 subtypes (e.g., the AUBA compounds) and for the GluK1 homomeric KAR (NS3763). These compounds are likely to be the starting point of further development of noncompetitive antagonists. Other modulators include the Joro spider toxin (JSTX) - blocking the unedited GluK2, Arachidonic acid, primarily blocking homomeric GluK2 and GluK1/ GluK2 receptors and Topiramate which inhibits excitatory neurotransmission also through actions on KAR (GluK1) and AMPARs (Lutz and Kenakin 1999).

mGluR Antagonists

Competitive antagonists acting on mGluRs prevent the closure of the two lobes of the extracellular binding pocket (the venus flytrap). Potent competitive antagonists for the Group I receptors (e.g., LY367366) are derived from the (S)-MCPG structure, while LY367385 is a selective mGlu1 antagonist. Most potent Group II antagonists are derived from L-CCG-I (e.g., LY341495) while antagonists with better selectivity could be obtained by derivatiza-tion of agonist LY354740, e.g., HYDIA and MGS0039. Extensive preclinical studies have been performed with the Group II selective antagonists showing antidepressant and anxiolytic-like effects. The Group III mGluRs still lack competitive antagonists with high potency and selectivity while compounds like MAP4, DCG-IV, and LY341495

function as antagonists with moderate potency. Due to the high similarity of the orthosteric binding site of the different mGluRs, the most promising strategy to selectively antagonize this group of receptors is by targeting the allosteric binding site(s) using NAMs.

Group I NAM mGlu1: The most commonly used mGlu1 antagonist is the noncompetitive antagonist CPCCOEt which is structurally unrelated to Glu and is binding in the TM domain of the receptor. More potent NAMs are YM-298198, BAY36-7620, and EM-TBPC, interacting in the same region of the receptor. Blockade of mGlu1, by ► antisense oligonucleotides, antibodies, and NAMs, has shown its involvement in modulation of nociception and chronic pain. A-841720 NAM, structurally different to previous mGlu1 NAMs, has also shown to be effective in models of ► nociception and is presently under development for pain treatment. Antagonists of mGlu1 have been postulated to have a therapeutic effect in ► anxiety disorders which has been confirmed by the potent mGlu1 NAM JNJ16259685.

Group I NAM mGlu5: Brain areas expressing mGlu5 receptors (limbic cortex, hippocampus, amygdala, and basal ganglia) are known to play an important role in emotion and motor controls, and mGlu5 was early recognized as a potential target for ► mood disorders and neu-rodegenerative diseases involving motor dysfunctions. SIB-1757 and SIB-1893 were the first selective mGlu5 NAMs to be identified. They were further developed and optimized into the more potent and selective MPEP which is the most widely used mGlu5 antagonist (a prototype for mGlu5 NAMs). mGlu5 NAMs, such as MPEP and its more selective derivative MTEP, show a clear anxiolytic and antidepressant-like profile in a wide range of preclinical behavioral models. In the search for mGlu5 NAMs, the known anxiolytic compound fenobam was identified, binding to the receptor at the same site as MPEP. After this observation several pharmaceutical companies have filed numerous patents on compounds acting as mGlu5 NAMs (divided into two major classes: acetylene- and nonacetylene-containing compounds). The mGlu5 NAM ADX-10059 recently completed a ► Phase-II trial in migraine with successful outcome. The same compound was also the first in class to show positive results in a Phase-II trial for gastroesophageal acid-reflux disease. Supported by mGlu5 expression in cortical and basal ganglia structures, mGlu5 NAMs have been shown to treat L-Dopa-induced ► dyskinesia in rodent and primate models. MPEP has also been shown to protect the nigrostriatal system against toxicity, thus having a neuro-protective function and a possibility to prevent disease development. Based on these indications, the AFQ-056

and ADX48621 compounds are in development for reducing L-Dopa-induced dyskinesias in ► Parkinson's disease. It has been suggested that the loss of FMRP (► Fragile X Mental Retardation Protein) will result in an enhanced mGlu5 signaling, and attenuation of mGlu5 activity is therefore believed to provide not only symptomatic relief but also disease modification in Fragile X syndrome. NPL-2009 (Fenobam), STX107, and AFQ-056 are all in development as potential therapies for this autistic disorder (Jaeschke et al. 2008).

Group II NAM: Preclinical studies in rodents are supportive of a therapeutic potential for mGlu2/3 NAM in mood disorders and as cognitive enhancers. A class of ► benzodiazepines (e.g., MNI135, RO676221, and RO718216) has been disclosed as potent and in vivo active mGlu2/3 NAM. The discovery of antagonists with selectivity for the two subtypes, mGlu2 and mGlu3, would also help to clarify the specific role of these receptors under physiological and pathological conditions.

Group III NAM: The recent identification of selective allosteric agonists for mGlu4, 7 and 8 will greatly help to facilitate the pharmacological characterization of these receptors and the discovery of selective NAMs. Very recently a class of pyridine compounds (MDIP and MMPIP) was identified as mGlu7 NAM. They are likely to help the clarification of the physiological role of mGlu7 in anxiety since controversial results were seen in mGlu7 knockout mice and in studies using the allosteric agonist AMN082.

Conclusions and Perspectives

The effort placed during the past decades on the characterization of the molecular properties of EEAs and their antagonists has been rewarded with the development of some of these ligands for different therapeutic opportunities. The field is however still challenging. Further basic research is required to understand the function of the glutamatergic synaptic cleft in its entirety, as well as to clarify the peculiarities and the plasticity of the glutama-tergic control on ► GABA neurons. Moreover, a number of Glu receptors and subunits are still missing selective ligands, and the definition of molecular determinants of receptor cross talk for mGluRs (e.g., mGlu2/5-HT2A) could bring new challenges for medicinal chemists and new tools for behavioral pharmacologists. The clinical development of several EAA receptor ligands (included in Table 1) has also increased the need for suitable PET ligands (positron emission tomography; an imaging technique using short-lived radioactive substances to show uptake and distribution of the substances in tissue) that could be used during the preparation of the different clinical trials and possibly could be of help both in diagnostic terms and to identify responders.

Proof of concept clinical studies for the different pharmacological targets brought forward by the glutama-tergic hypothesis are certainly long awaited. They will help to understand if efficacy and tolerability of the pharmacotherapy of both schizophrenia and depression (McArthur and Borsini 2008) will be substantially improved in future years.

If there is, however, an achievement that already stands out because of the long-term impact it will hopefully have on the quality of life of the patients, this must be the observation of the effects of mGlu5 antagonists in

► Fragile X. The concrete hope of a cure has increased also the interest for the early diagnosis and for a better understanding of the disease progression during the first years of life. This is certainly one of the best examples of a successful molecular approach to the therapy of neurode-velopmental brain disorders.


► Allosteric Modulator(s)

► Allosteric Site

► Alternative Splicing

Alzheimer Disease

► AMPA Receptor

► Antagonist

► Antidepressant

► Antipsychotics

► Antisense Oligonucleotides

► Anxiolytic

► Benzodiazepines

► Cognitive Enhancers

► Cognitive Impairment(s)

► Depression

► Desensitization

► Dyskinesia

► G protein Coupled Receptor

► G-protein Coupled Inwardly Rectifying Potassium Channels (GIRK channels)

► GABA Receptors

► Glutamate Receptors

► Glycine Transporter 1

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