Halogenated derivatives of aromatic amino acids exhibit balanced antiglutamatergic actions: potential applications for the treatment of neurological and neuropsychiatric disorders.
Glutamate, the major excitatory neurotransmitter, is critical for normal brain development and function. Both extremes of glutamate receptor activity are detrimental for the brain. Glutamate's role in excitotoxicity has driven the search for receptor antagonists as neuroprotective agents, most of which have failed to achieve clinical, i.e. efficacious and safe, neuroprotection. High selectivity and potency provide potential explanations for this failure. For example, targeting individual glutamate receptor subtypes leaves other pathways of glutamatergic excitotoxicity intact. Furthermore, potent depression of glutamate receptor activity causes clinical side effects, such as the symptoms of schizophrenia produced by NMDA receptor antagonists. To produce efficacious neuroprotection devoid of significant side effects, it may be necessary to normalize the function of all components of the glutamatergic system, instead of blocking a single type of glutamate receptors. Halogenated derivatives of aromatic amino acids modulate glutamatergic activity via multiple pre- and postsynaptic actions with moderate efficacy. In addition, these compounds may trap hydroxyl radicals and facilitate hydroxyl radical-impaired glutamate uptake. Their balanced polyvalent action may overcome the limitations of previously tested glutamatergic agents and provide a basis for their use in the treatment of neurological and neuropsychiatric disorders. The properties of this class of compounds and relevant patents are reviewed in this article.
Martynyuk
Anatoly E
AE
Department of Anesthesiology, University of Florida, Gainesville, Florida 32610-0254, USA. AMartynyuk@anest.ufl.edu
Seubert
Christoph N
CN
Yarotskyy
Viktor
V
Glushakov
Alexander V
AV
Gravenstein
Nikolaus
N
Sumners
Colin
C
Dennis
Donn M
DM
D000818:Animals; D001921:Brain / Q000378:metabolism; D001927:Brain Diseases / Q000188:drug therapy; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D017665:Hydroxyl Radical; D001523:Mental Disorders / Q000188:drug therapy; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D009435:Synaptic Transmission / Q000187:drug effects; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use
D018691:Excitatory Amino Acid Antagonists; D018696:Neuroprotective Agents; D017665:Hydroxyl Radical; D018698:Glutamic Acid; D014443:Tyrosine; D010649:Phenylalanine; C082610:3,5-dibromotyrosine