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Titolo:
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
Autore:
PARSONS CG; QUACK G; BRESINK I; BARAN L; PRZEGALINSKI E; KOSTOWSKI W; KRZASCIK P; HARTMANN S; DANYSZ W;
Indirizzi:
MERZ & CO,DEPT PHARMACOL,ECKENHEIMER LANDTRASSSE 100-104 D-60318 FRANKFURT GERMANY PAN,INST PHARMACOL KRAKOW POLAND INST PSYCHIAT & NEUROL,DEPT PHARMACOL WARSAW POLAND
Titolo Testata:
Neuropharmacology
fascicolo: 10, volume: 34, anno: 1995,
pagine: 1239 - 1258
SICI:
0028-3908(1995)34:10<1239:COTPKA>2.0.ZU;2-H
Fonte:
ISI
Lingua:
ENG
Soggetto:
METHYL-D-ASPARTATE; AMINO-ACID RECEPTORS; NEUROPROTECTIVE PROPERTIES; GLUTAMATE; MEMANTINE; NEURONS; BRAIN; ISCHEMIA; CHANNEL; SEIZURES;
Keywords:
N-METHYL-D-ASPARTATE (NMDA); NMDA RECEPTORS; AMINO-ADAMANTANES; AMANTADINE; MEMANTINE; (+)-MK-801; KETAMINE; DEXTRORPHAN; DEXTROMETHORPHAN; PHENCYCLIDINE; PATCH CLAMP; ELECTROPHYSIOLOGY; ON-OFF KINETICS; BINDING; CONVULSIONS; PENTYLENETETRAZOL; MAXIMAL ELECTROSHOCK (MES); ATAXIA; THERAPEUTIC INDEX;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Science Citation Index Expanded
Citazioni:
67
Recensione:
Indirizzi per estratti:
Citazione:
C.G. Parsons et al., "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", Neuropharmacology, 34(10), 1995, pp. 1239-1258

Abstract

The amino-adamantane derivatives memantine (1-amino-3,5-dimethyladamantane) and amantadine (1-amino-adamantane) are relatively low affinity, uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists whichhave 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 preclinicalmodels of epilepsy by assessing the potency, kinetics and voltage-dependency of open channel blockade for a series antagonists in vitro andcomparing these effects to anticonvulsive and motor impairment activity in vivo. The compounds tested were memantine, amantadine, 14 other amino-adamantanes, (+)-MK-801, ketamine, dextrorphan, dextromethorphanand 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 potentantagonists 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), tau(on) estimated at IC50 is perhaps a more meaningful measure of onset kinetics at equieffective concentrations and was alsowell correlated to potency (r = -0.863). All amino-adamantanes testedwere 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[H-3](+)-MK-801 binding and their in vivo activity against maximal electroshock (MES) and pentylenetetrazol (PTZ) induced tonic convulsionsand NMDA-induced lethality in mice. Memantine and four other amino-adamantanes with somewhat lower potency and faster blocking kinetics hadbetter 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 potencythan memantine actually had poorer therapeutic indices (TI less than or equal to 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 totherapeutic indices (traction r = -0.790, rotarod r = -0.797) i.e. the less potent uncompetitive antagonists had worse therapeutic indices. The data from the present study do not lend support to the idea that low affinity, open channel NMDA receptor blockers are also effective in models of epilepsy at doses having little effect on physiological processes. It should be stressed that these data do not contradict the known therapeutic safety of memantine and amantadine in dementia and Parkinson's disease respectively. Thus the good clinical profile of memantine in dementia has been attributed not only to its fast blocking/unblocking kinetics but also to its strong voltage-dependency. These biophysical properties may allow therapeutically-relevant concentrations to block chronic, low level pathological activation of NMDA receptors whilst leaving their synaptic activation intact. Precisely these properties may also underlie the poor therapeutic indices seen in the present study on antiepileptic activity due to the synaptic nature of both seizures and normal glutamatergic transmission.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 03/04/20 alle ore 14:03:33