Comparison of the potency, kinetics and voltage-dependency of a series of uncompetitive NMDA receptor antagonists in vitro with anticonvulsive and motor impairment activity in vivo

• Published in: Neuropharmacology 1995-10, Vol.34 (10), p.1239-1258
• Main Authors: Parsons, C.G., Quack, G., Bresink, I., Baran, L., Przegalinski, E., Kostowski, W., Krzascik, P., Hartmann, S., Danysz, W.
• Format: Article
• Language: English
• Subjects: (+)-MK-801; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid - pharmacology; amantadine; Amantadine - pharmacology; amino-adamantanes; Animals; Anticonvulsants - pharmacology; Anticonvulsants. Antiepileptics. Antiparkinson agents; ataxia; binding; Binding, Competitive; Biological and medical sciences; Cells, Cultured - drug effects; convulsions; dextromethorphan; dextrorphan; Dizocilpine Maleate - pharmacology; electrophysiology; In Vitro Techniques; ketamine; Kinetics; Male; maximal electroshock (MES); Medical sciences; memantine; Mice; N-Methyl-D-aspartate (NMDA); Neuropharmacology; NMDA receptors; on-off kinetics; patch clamp; Patch-Clamp Techniques; pentylenetetrazol; Pharmacology. Drug treatments; phencyclidine; Rats; Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors; Receptors, N-Methyl-D-Aspartate - metabolism; therapeutic index
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/0028-3908(95)00092-K

The amino-adamantane derivatives memantine (l-amino-3,5-dimethyladamantane) and amantadine (1-amino-adamantane) are relatively low affinity, uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists which have been used clinically in the treatment of dementia and Parkinson's disease respectively for several years without serious side effects. The aim of this study was to test whether memantine, amantadine and other low affinity uncompetitive NMDA receptor antagonists also have better therapeutic indices than high affinity antagonists in preclinical models of epilepsy by assessing the potency, kinetics and voltage-dependency of open channel blockade for a series antagonists in vitro and comparing these effects to anticonvulsive and motor impairment activity in vivo. The compounds tested were memantine, amantadine, 14 other amino-adamantanes, (+)-MK-801, ketamine, dextrorphan, dextromethorphan and phencyclidine. The offset kinetics of open-channel blockade assessed with whole cell patch clamp recordings from cultured superior colliculus neurones were highly correlated to potency i.e. the less potent antagonists showed faster unblocking kinetics ( K off , r = 0.904). Although, onset kinetics as assessed by K on were not correlated to potency ( r = 0.023), τ on estimated at IC 50 is perhaps a more meaningful measure of onset kinetics at equieffective concentrations and was also well correlated to potency ( r = − 0.863). All amino-adamantanes tested were strongly voltage-dependent. There was also a good correlation between the in vitro potencies of uncompetitive NMDA receptor antagonists assessed with patch clamp recordings and displacement of equilibrium [ 3H](+)-MK-801 binding and their in vivo activity against maximal ehxtroshock (MES) and pentylenetetrazol (PTZ) induced tonic convulsions and NMDA-induced lethality in mice. Memantine and four other amino-adamantanes with somewhat lower potency and faster blocking kinetics had better therapeutic indices (ED 50 rotarod and traction reflex over ED 50 in MES-induced convulsions; TI = 2–4) than substances with higher affinity such as ketamine, dextrorphan and (+)-MK-801 ( TI < 2). However, amantadine and several other amino-adamantanes with lower potency than memantine actually had poorer therapeutic indices ( TI ⩽ 0.5) which may have been due to additional actions at other ion channels or receptors at the doses necessary to protect against seizures. In fact, ED 50 in the MES test was negatively-correlated t