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Titolo:
Amino-alkyl-cyclohexanes are novel uncompetitive NMDA receptor antagonistswith strong voltage-dependency and fast blocking kinetics: in vitro and invivo characterization
Autore:
Parsons, CG; Danysz, W; Bartmann, A; Spielmanns, P; Frankiewicz, T; Hesselink, M; Eilbacher, B; Quack, G;
Indirizzi:
Merz & Co, Dept Pharmacol, D-60318 Frankfurt, Germany Merz & Co Frankfurt Germany D-60318 harmacol, D-60318 Frankfurt, Germany
Titolo Testata:
NEUROPHARMACOLOGY
fascicolo: 1, volume: 38, anno: 1999,
pagine: 85 - 108
SICI:
0028-3908(199901)38:1<85:AANUNR>2.0.ZU;2-0
Fonte:
ISI
Lingua:
ENG
Soggetto:
METHYL-D-ASPARTATE; PHENCYCLIDINE-LIKE DRUGS; CHANNEL BLOCKERS; HIPPOCAMPAL-NEURONS; PATCH-CLAMP; SELECTIVE VULNERABILITY; ANTICONVULSANT MK-801; ACTIVATED CHANNELS; RAT HIPPOCAMPAL; MEMANTINE;
Keywords:
uncompetitive N-methyl-D-aspartate receptor antagonist; subtypes; amino-alkyl-cyclohexane; patch clamp; excitotoxicity; cortical cultures; hypoglycaemia; hypoxia; hipppocampal slices; Xenopus oocytes; MES-convulsions; microdialysis;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
79
Recensione:
Indirizzi per estratti:
Indirizzo: Parsons, CG MerzGermanyDept Pharmacol, Eckenheimer Landstr 100-104, D-60318 Frankfurt, Merz & Co Eckenheimer Landstr 100-104 Frankfurt Germany D-60318
Citazione:
C.G. Parsons et al., "Amino-alkyl-cyclohexanes are novel uncompetitive NMDA receptor antagonistswith strong voltage-dependency and fast blocking kinetics: in vitro and invivo characterization", NEUROPHARM, 38(1), 1999, pp. 85-108

Abstract

The present study characterized the in vitro NMDA receptor antagonistic properties of novel amino-alkyl-cyclohexane derivatives and compared these effects with their ability to block excitotoxicity in vitro and MES-induced convulsions in vivo. The 36 amino-alkyl-cyclohexanes tested displaced [H-3]-(+)-MK-801 binding to rat cortical membranes with K(i)s between 1.5 and 143mu M. Current responses of cultured hippocampal neurones to NMDA were antagonized by the same compounds with a wide range of potencies (IC(50)s of 1.3-245 mu M, at -70 mV) in a use- and strongly voltage-dependent manner (Delta 0.55-0.87). The offset kinetics of NMDA receptor blockade was correlatedwith equilibrium affinity (Corr Coeff. 0.87 P < 0.0001). As an example, MRZ 2/579 (1-amino-1,3,3,5,5-pentamethyl-cyclohexane HCl) had similar blocking kinetics to those previously reported for memantine (K-on 10.67 +/- 0.09 x 10(4) M-1 s(-1), K-off 0.199 +/- 0.02 s(-1), K-d = K-off/K-on = 1.87 mu Mc.f. IC50 of 1.29 mu M). Most amino-alkyl-cyclohexanes were protective against glutamate toxicity in cultured cortical neurones (e.g. MRZ 2/579 IC50 2.16 +/- 0.03 mu M). Potencies in the three in vitro assays showed a relatively strong cross correlation (all corr. coeffs. > 0.72, P < 0.0001). MRZ 2/579 was also effective in protecting hippocampal slices against 7 min, hypoxia/hypoglycaemia-induced reduction of fEPSP amplitude in CA1 with an EC50of 7.01 +/- 0.24 mu M. MRZ 2/579 showed no selectivity between NMDA receptor subtypes expressed in Xenopus oocytes but was somewhat more potent than in patch clamp experiments-IC(50)s of 0.49 +/- 0.11, 0.56 +/- 0.01 mu M, 0.42 +/- 0.04 and 0.49 +/- 0.06 mu M on NR1a/2A /2B, /2C and 2/D, respectively. Ln contrast, memantine and amantadine were both 3-fold more potent at NR1a/2C and NR1a/2D than NR1a/2A receptors. All Merz amino-alkyl-cyclohexane derivatives inhibited MES-induced convulsions in mice with ED(50)s ranging from 3.6 to 130 mg/kg i.p. The in vivo and in vitro potencies correlated indicating similar access of most compounds to the CNS. MRZ 2/579 administered at 10 mg/kg resulted in peak plasma concentrations of 5.3 and 1.4 mu M following i.v. and p.o. administration respectively, which then declined witha half life of around 170-210 min. Analysis of A.U.C. concentrations indicates a p.o./i.v. bioavailability ratio for MRZ 2/579 of 60%. MRZ 2/579 injected i.p. at a dose of 5 mg/kg resulted in peak brain extracellular fluid (ECF) concentrations of 0.78 mu M (brain microdialysates). Of the compounds tested MRZ 2/579, 2/615, 2/632, 2/633, 2/639 and 2/640 had affinities, kinetics and voltage-dependency most similar to those of memantine and had goodtherapeutic indices against MES-induced convulsions. We predict that theseamino-alkyl-cyclohexanes, which all had methyl substitutions at R1, R2, and R5, at least one methyl or ethyl at R3 or R4 and a charged a;nino-containing substitution at R6, could be useful therapeutics in a wide rang of CNS disorders proposed to involve disturbances of glutamatergic transmission. (C) 1999 Elsevier Science Ltd. All rights reserved.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 06/04/20 alle ore 05:44:50