Lack of effect of the novel anticonvulsant SB-204269 on voltage-dependent currents in neurones cultured front rat hippocampus

被引：6

作者：

Caesar, M ^{[1
]}

Evans, ML ^{[1
]}

Benham, CD ^{[1
]}

机构：

[1] SmithKline Beecham Pharmaceut, Neurosci Res, Harlow CM19 5AW, Essex, England

来源：

NEUROSCIENCE LETTERS | 1999年 / 271卷 / 01期

关键词：

anticonvulsants; sodium channels; epilepsy; hippocampus; SB-204269; lamotrigine;

D O I：

10.1016/S0304-3940(99)00514-5

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

The novel anticonvulsant SB-204269 inhibits epileptiform afterdischarges induced by high K+ in rat hippocampal slices. Its effects on voltage-gated Na+ currents, measured from cultured hippocampal neurones using whole cell patch clamp, were compared to the effects of existing anticonvulsants. SB-204269 produced no significant tonic block of Na+ currents nor any voltage-dependent and frequency-dependent block at doses 50 to 500 fold higher than its anticonvulsant EC50 of 0.2 mu M. In contrast, lamotrigine, phenytoin and carbamazepine at 50 mu M, blocked Na+ currents in a voltage-dependent manner. SB-204269 also had no effect on action potential discharges evoked by elevating external Kf. These data suggest that direct blockade of voltage-gated channels does not contribute to the anticonvulsant properties of SB-204269 and further support the hypothesis that this compound has a novel mechanism of action. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved.

引用

页码：57 / 60

页数：4

共 12 条

[1] Synthesis of novel trans-4-(substituted-benzamido)-3,4-dihydro-2H-benzo[b]-pyran-3-ol derivatives as potential anticonvulsant agents with a distinctive binding profile [J].

Chan, WN ;

Evans, JM ;

Hadley, MS ;

Herdon, HJ ;

Jerman, JC ;

Morgan, HKA ;

Stean, TO ;

Thompson, M ;

Upton, N ;

Vong, AK .

JOURNAL OF MEDICINAL CHEMISTRY, 1996, 39 (23) :4537-4539

[2] Characterization of the binding of [H-3]-SB-204269, a radiolabelled form of the new anticonvulsant SB-204269, to a novel binding site in rat brain membranes [J].

Herdon, HJ ;

Jerman, JC ;

Stean, TO ;

Middlemiss, DN ;

Chan, WN ;

Vong, AK ;

Evans, JM ;

Thompson, M ;

Upton, N .

BRITISH JOURNAL OF PHARMACOLOGY, 1997, 121 (08) :1687-1691

[3]

LANG DG, 1993, J PHARMACOL EXP THER, V266, P829

[4]

PECK AW, 1991, EPILEPSIA S2, V32, P9

[5]

RAGSDALE DS, 1991, MOL PHARMACOL, V40, P756

[6]

ROGAWSKI MA, 1990, PHARMACOL REV, V42, P223

[7] Profile of SB-204269, a mechanistically novel anticonvulsant drug, in rat models of focal and generalized epileptic seizures [J].

Upton, N ;

Blackburn, TP ;

Campbell, CA ;

Cooper, D ;

Evans, ML ;

Herdon, HJ ;

King, PD ;

Ray, AM ;

Stean, TO ;

Chan, WN ;

Evans, JM ;

Thompson, M .

BRITISH JOURNAL OF PHARMACOLOGY, 1997, 121 (08) :1679-1686

[8] MECHANISMS OF ACTION OF NEW ANTIEPILEPTIC DRUGS - RATIONAL DESIGN AND SERENDIPITOUS FINDINGS [J].

UPTON, N .

TRENDS IN PHARMACOLOGICAL SCIENCES, 1994, 15 (12) :456-463

[9]

WAMIL A W, 1991, Epilepsia, V32, P20

[10] Developments at the Norman Lockyer Observatory [J].

White, G .

ASTRONOMY & GEOPHYSICS, 1997, 38 (06) :9-9

← 1 2 →