Biomaterial Database

Low affinity use-dependent NMDA receptor antagonists show promise for clinical development. 2000

G C Palmer, and D Widzowski

Astra Zeneca R&D Boston, Rochester, New York, USA. eugene.palmer@astrazeneca.com

The success of the low affinity use-dependent NMDA receptor antagonists to reach clinical trials can be readily attributed to their wider margins of safety and lack of neurotoxicity at higher doses. Several mechanistic differences distinguish the low affinity from the high affinity use-dependent antagonists: 1) Differential regional affinities for the various NMDA receptor subtypes; 2) The static receptor blockade due to the faster on/off rate receptor kinetics which limit, but do not totally prevent the amount of Ca+2 entry into the cell during glutamate-induced depolarization; and 3) Rapid egress of the compounds from the ion channel during recovery resulting in less membrane trapping between transmission pulses. Advanced clinical trials are in progress for the following indications: epilepsy, stroke, head trauma, tardive dyskinesia, pain plus Parkinson's, Huntington's and Alzheimer's diseases.

UI	MeSH Term	Description	Entries
D004827	Epilepsy	A disorder characterized by recurrent episodes of paroxysmal brain dysfunction due to a sudden, disorderly, and excessive neuronal discharge. Epilepsy classification systems are generally based upon: (1) clinical features of the seizure episodes (e.g., motor seizure), (2) etiology (e.g., post-traumatic), (3) anatomic site of seizure origin (e.g., frontal lobe seizure), (4) tendency to spread to other structures in the brain, and (5) temporal patterns (e.g., nocturnal epilepsy). (From Adams et al., Principles of Neurology, 6th ed, p313)	Aura,Awakening Epilepsy,Seizure Disorder,Epilepsy, Cryptogenic,Auras,Cryptogenic Epilepsies,Cryptogenic Epilepsy,Epilepsies,Epilepsies, Cryptogenic,Epilepsy, Awakening,Seizure Disorders
D006259	Craniocerebral Trauma	Traumatic injuries involving the cranium and intracranial structures (i.e., BRAIN; CRANIAL NERVES; MENINGES; and other structures). Injuries may be classified by whether or not the skull is penetrated (i.e., penetrating vs. nonpenetrating) or whether there is an associated hemorrhage.	Frontal Region Trauma,Head Injuries,Head Trauma,Occipital Region Trauma,Parietal Region Trauma,Temporal Region Trauma,Craniocerebral Injuries,Crushing Skull Injury,Forehead Trauma,Head Injuries, Multiple,Head Injury, Minor,Head Injury, Open,Head Injury, Superficial,Injuries, Craniocerebral,Injuries, Head,Multiple Head Injuries,Occipital Trauma,Open Head Injury,Superficial Head Injury,Trauma, Head,Craniocerebral Injury,Craniocerebral Traumas,Crushing Skull Injuries,Forehead Traumas,Frontal Region Traumas,Head Injuries, Minor,Head Injuries, Open,Head Injuries, Superficial,Head Injury,Head Injury, Multiple,Head Traumas,Injuries, Minor Head,Injuries, Multiple Head,Injuries, Open Head,Injuries, Superficial Head,Injury, Craniocerebral,Injury, Head,Injury, Minor Head,Injury, Multiple Head,Injury, Open Head,Injury, Superficial Head,Minor Head Injuries,Minor Head Injury,Multiple Head Injury,Occipital Region Traumas,Occipital Traumas,Open Head Injuries,Parietal Region Traumas,Region Trauma, Frontal,Region Trauma, Occipital,Region Trauma, Parietal,Region Traumas, Frontal,Region Traumas, Occipital,Region Traumas, Parietal,Skull Injuries, Crushing,Skull Injury, Crushing,Superficial Head Injuries,Temporal Region Traumas,Trauma, Craniocerebral,Trauma, Forehead,Trauma, Frontal Region,Trauma, Occipital,Trauma, Occipital Region,Trauma, Parietal Region,Trauma, Temporal Region,Traumas, Craniocerebral,Traumas, Forehead,Traumas, Frontal Region,Traumas, Head,Traumas, Occipital,Traumas, Occipital Region,Traumas, Parietal Region,Traumas, Temporal Region
D006801	Humans	Members of the species Homo sapiens.	Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
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
D019636	Neurodegenerative Diseases	Hereditary and sporadic conditions which are characterized by progressive nervous system dysfunction. These disorders are often associated with atrophy of the affected central or peripheral nervous system structures.	Degenerative Diseases, Nervous System,Degenerative Diseases, Central Nervous System,Degenerative Diseases, Neurologic,Degenerative Diseases, Spinal Cord,Degenerative Neurologic Diseases,Degenerative Neurologic Disorders,Nervous System Degenerative Diseases,Neurodegenerative Disorders,Neurologic Degenerative Conditions,Neurologic Degenerative Diseases,Neurologic Diseases, Degenerative,Degenerative Condition, Neurologic,Degenerative Conditions, Neurologic,Degenerative Neurologic Disease,Degenerative Neurologic Disorder,Neurodegenerative Disease,Neurodegenerative Disorder,Neurologic Degenerative Condition,Neurologic Degenerative Disease,Neurologic Disease, Degenerative,Neurologic Disorder, Degenerative,Neurologic Disorders, Degenerative
D020521	Stroke	A group of pathological conditions characterized by sudden, non-convulsive loss of neurological function due to BRAIN ISCHEMIA or INTRACRANIAL HEMORRHAGES. Stroke is classified by the type of tissue NECROSIS, such as the anatomic location, vasculature involved, etiology, age of the affected individual, and hemorrhagic vs. non-hemorrhagic nature. (From Adams et al., Principles of Neurology, 6th ed, pp777-810)	Apoplexy,Cerebral Stroke,Cerebrovascular Accident,Cerebrovascular Apoplexy,Vascular Accident, Brain,CVA (Cerebrovascular Accident),Cerebrovascular Accident, Acute,Cerebrovascular Stroke,Stroke, Acute,Acute Cerebrovascular Accident,Acute Cerebrovascular Accidents,Acute Stroke,Acute Strokes,Apoplexy, Cerebrovascular,Brain Vascular Accident,Brain Vascular Accidents,CVAs (Cerebrovascular Accident),Cerebral Strokes,Cerebrovascular Accidents,Cerebrovascular Accidents, Acute,Cerebrovascular Strokes,Stroke, Cerebral,Stroke, Cerebrovascular,Strokes,Strokes, Acute,Strokes, Cerebral,Strokes, Cerebrovascular,Vascular Accidents, Brain