New AMPA antagonists in epilepsy.
BACKGROUND
Epilepsy is a common neurological disorder; however, its therapy is not satisfactory because a large number of patients suffer from refractory seizures and/or has a low quality of life due to antiepileptic drug (AED) side effects. Glutamate is the major excitatory neurotransmitter in the brain, AMPA receptors (AMPARs) represent a validated target for AEDs' development. Evidences support their role during seizures and neurodegeneration. Development of AMPAR ligands has led to two different branches of research, with the identification of competitive and noncompetitive antagonists.


METHODS
We herein describe the architecture of AMPAR and the main structure-activity relationships of antagonists. Finally, we report the effects of AMPAR antagonists in preclinical models and clinical trials in epileptic patients. We reviewed the most relevant research in the field, focusing on research advances for the oldest AMPA antagonists and the new most promising molecules identified.


CONCLUSIONS
Overall, the development of AMPAR antagonists confirms their great clinical potential; their arrival to clinical practice has been slowed down by their unfavorable pharmacokinetic profile and tolerability; however, their clinical use might be justified by their efficacy and the new drugs developed such as perampanel have been greatly ameliorated from both points of view.
University "Magna Graecia" of Catanzaro, School of Medicine, Science of Health Department, Catanzaro, Italy.
Emilio
E
Russo
Rosaria
R
Gitto
Rita
R
Citraro
Alba
A
Chimirri
Giovambattista
G
De Sarro
D000818:Animals; D000927:Anticonvulsants / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D002986:Clinical Trials as Topic; D004195:Disease Models, Animal; D016503:Drug Delivery Systems; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004827:Epilepsy / Q000188:drug therapy* / Q000503:physiopathology; D006801:Humans; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
D000927:Anticonvulsants; D018091:Receptors, AMPA