Alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA)-type glutamate receptors mediate most of the excitatory neurotransmission and play a key role in synaptic plasticity in the mammalian central nervous system (CNS). Positive allosteric modulators (agonists) facilitate hippocampal long-term potentiation, a mechanism associated with memory storage and consolidation. AMPA receptor agonists enhance glutamatergic neurotransmission. Several AMPA receptor agonists are in advanced clinical evaluation in CNS diseases such as cognitive impairment (Alzheimer’s disease) as well as attention-deficit hyperactivity disorder, schizophrenia and depression. Negative allosteric modulators function as antagonists of the AMPA neuronal excitatory glutamate receptor and may have neuroprotective and anticonvulsant activity. Blocking the AMPA receptor can protect the brain from apoptotic and necrotic cell death by preventing neuronal excitotoxicity during pathophysiological activation of the glutamatergic neurons. Among the clinical indications under investigations for AMPA receptor antagonists are neuropathic pain and migraine, epilepsy, Parkinson’s disease and amyotrophic lateral sclerosis. Multiple sclerosis is also regarded as a clinical indication. Several companies are engaged in the advanced clinical development of AMPA receptor antagonists.

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