Inhibitors of AMPA and Kainate Receptors

Abstract

The glutamate receptor system is implicated in the development and maintenance of epileptic seizures, and animal studies have disclosed potent anticonvulsant activity of a number of inhibitors of AMPA and/or kainate (KA) receptor activity. These results make such inhibitors potential future antiepileptic drugs. Different series of compounds with inhibitory activity towards AMPA receptors have been developed. Most of these inhibitors are structurally derived from AMPA, quinoxalinedione or 2,3-benzodiazepine. In contrast, only a limited number of inhibitors of KA receptor activity have been developed, most of which contain quinoxalinedione or decahydroisoquinoline skeletons. In spite of promising anticonvulsant activity in various animal model studies, no AMPA/KA receptor inhibitors are in clinical use against epilepsy today. Based on molecular biology studies, AMPA and KA receptors are at present divided into four and five subtypes, respectively, and attempts to develop subtype selective compounds have been initiated. Future studies and development of such compounds will indicate whether AMPA/KA receptor inhibition is a feasible therapeutic strategy for the treatment of epilepsy.

Ionotropic Glutamate Receptors & CNS Disorders

“…To date, AMPARs have been implicated in several neurodevelopmental disorders, such as Fragile-X mental retardation [140][141][142][143][144][145] and schizophrenia [145][146][147], neurodegenerative conditions, such as Alzheimer's disease [145,147], motor neuron disease or Amyotrophic Lateral Sclerosis (ALS) [148][149][150][151][152][153], stroke [146,149,[154][155][156][157][158][159] and parkinsonism [146,147,[160][161][162][163][164], as well as contributing to the proliferation of glioblastoma tumors [165][166][167][168]. Furthermore, AMPARs have also been suggested to fulfill roles in depression [146,147,160] as well as the seizure spread and the neuronal damage associated with epilepsy [169] [158,[170][171][172] and Rasmussen's syndrome [173,…”

AMPA receptor ligands: Synthetic and pharmacological studies of polyamines and polyamine toxins

“…83 The same decahydroisoquinoline scaffold has also led to potent and selective antagonists at the KAR. 84 Similarly, a range of non-competitive AMPAR antagonists have been developed (Fig. 5); one important example being the previously mentioned GYKI 53784 (14), which is the active enantiomer of GYKI 53655, belonging to the 2,3-benzodiazepine class of AMPAR antagognists.…”

Zielstrukturen für Antiepileptika: Molekulare Neurobiologie der Epilepsie

“…Der Kationenkanal des NMDA-Rezeptors ist recht unselektiv und erlaubt sowohl Na + -, K + -als auch Ca 2+ -Ionen der Durchfluss. NMDA-Rezeptoren haben zwei besondere Eigenschaften: Unter den kommerziell erhältlichen Antiepileptika finden sich bislang keine selektiven Antagonisten der Glutamatrezeptoren, jedoch einige Substanzen, die wenigstens zum Teil über diese Rezeptoren agieren [11,12]. Felbamat inhibiert in klinisch relevanten Konzentrationen subtypspezifisch NMDA-Rezeptoren, die eine NR2B-Untereinheit enthalten und bevorzugt im Vorderhirn exprimiert werden, hat aber auch noch andere Wirkorte.…”