Biomaterial Database

Low affinity channel blocking (uncompetitive) NMDA receptor antagonists as therapeutic agents--toward an understanding of their favorable tolerability. 2000

M A Rogawski

Neuronal Excitability Section, Epilepsy Research Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892-1408, USA. rogawski@nih.gov

Studies in experimental models have suggested that NMDA receptor antagonists may have utility in the treatment of a wide variety of neurological and psychiatric disorders. However, clinical trials have not been encouraging largely because the antagonists evaluated to date have exhibited unacceptable neurobehavioral side effects. In animals, therapeutic doses of some low-affinity channel blocking (uncompetitive) NMDA receptor antagonists are associated with less gross neurological impairment and behavioral toxicity than other types of NMDA receptor antagonists. Favorable clinical experiences with several such agents has bolstered confidence in the neurotherapeutic potential of low affinity NMDA antagonists. This article reviews current research attempting to explain the improved tolerability of such antagonists. While no single mechanism appears to account for the reduced toxicity of such agents, kinetic properties, particularly rapid blocking rate, seem to be of key importance. Other factors include partial trapping, reduced agonist-independent (closed channel) block, subunit selectivity (particularly for receptors that do not contain the NR2A subunit), combined block at allosteric (voltage-independent) sites, and synergistic therapeutic effects produced by additional actions at receptor targets apart from NMDA receptors (e.g., weak positive allosteric modulation of GABA(A) receptors or state-dependent Na+ channel block).

UI	MeSH Term	Description	Entries
D007700	Kinetics	The rate dynamics in chemical or physical systems.
D009422	Nervous System Diseases	Diseases of the central and peripheral nervous system. This includes disorders of the brain, spinal cord, cranial nerves, peripheral nerves, nerve roots, autonomic nervous system, neuromuscular junction, and muscle.	Neurologic Disorders,Nervous System Disorders,Neurological Disorders,Disease, Nervous System,Diseases, Nervous System,Disorder, Nervous System,Disorder, Neurologic,Disorder, Neurological,Disorders, Nervous System,Disorders, Neurologic,Disorders, Neurological,Nervous System Disease,Nervous System Disorder,Neurologic Disorder,Neurological Disorder
D011485	Protein Binding	The process in which substances, either endogenous or exogenous, bind to proteins, peptides, enzymes, protein precursors, or allied compounds. Specific protein-binding measures are often used as assays in diagnostic assessments.	Plasma Protein Binding Capacity,Binding, Protein
D000818	Animals	Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA.	Animal,Metazoa,Animalia
D001665	Binding Sites	The parts of a macromolecule that directly participate in its specific combination with another molecule.	Combining Site,Binding Site,Combining Sites,Site, Binding,Site, Combining,Sites, Binding,Sites, Combining
D016194	Receptors, N-Methyl-D-Aspartate	A class of ionotropic glutamate receptors characterized by affinity for N-methyl-D-aspartate. NMDA receptors have an allosteric binding site for glycine which must be occupied for the channel to open efficiently and a site within the channel itself to which magnesium ions bind in a voltage-dependent manner. The positive voltage dependence of channel conductance and the high permeability of the conducting channel to calcium ions (as well as to monovalent cations) are important in excitotoxicity and neuronal plasticity.	N-Methyl-D-Aspartate Receptor,N-Methyl-D-Aspartate Receptors,NMDA Receptor,NMDA Receptor-Ionophore Complex,NMDA Receptors,Receptors, NMDA,N-Methylaspartate Receptors,Receptors, N-Methylaspartate,N Methyl D Aspartate Receptor,N Methyl D Aspartate Receptors,N Methylaspartate Receptors,NMDA Receptor Ionophore Complex,Receptor, N-Methyl-D-Aspartate,Receptor, NMDA,Receptors, N Methyl D Aspartate,Receptors, N Methylaspartate
D018691	Excitatory Amino Acid Antagonists	Drugs that bind to but do not activate excitatory amino acid receptors, thereby blocking the actions of agonists.	Amino Acids, Excitatory, Antagonists,Excitatory Amino Acid Antagonist,Glutamate Antagonist,Glutamate Antagonists,Glutamate Receptor Antagonist,Amino Acid Antagonists, Excitatory,Antagonists, Excitatory Amino Acid,EAA Antagonists,Glutamate Receptor Antagonists,Antagonist, Glutamate,Antagonist, Glutamate Receptor,Antagonists, EAA,Antagonists, Glutamate,Antagonists, Glutamate Receptor,Receptor Antagonist, Glutamate,Receptor Antagonists, Glutamate