Effects of Ca2+ and Na+ channel inhibitors in vitro and in global cerebral ischaemia in vivo.
In the present study we have examined the effects of the small organic molecules: NNC 09-0026 ((-)-trans-1-butyl-4-(4-dimethylaminophenyl)-3-[(4-trifluoromethyl-ph eno xy) methyl] piperidine dihydrochloride); SB 201823-A (4-[2-(3,4-dichlorophenoxy)ethyl]-1-pentyl piperidine hydrochloride); NS 649 (2-amino-1-(2,5-dimethoxyphenyl)-5-trifluoromethyl benzimidazole); CNS 1237 (N-acenaphthyl-N'-4-methoxynaphth-1-yl guanidine) and riluzole on human omega-conotoxin sensitive N-type voltage-dependent Ca2+ channel currents (ICa) expressed in HEK293 cells, on Na+ channel currents (INa) in acutely isolated cerebellar Purkinje neurones in vitro and in the gerbil model of global cerebral ischaemia in vivo. Estimated IC50 values for steady-state inhibition of ICa were as follows; NNC 09-0026, 1.1 microM; CNS 1237, 4.2 microM; SB 201823-A, 11.2 microM; NS 649, 45.7 microM and riluzole, 233 microM. Estimated IC50 values for steady-state inhibition of Na+ channel currents were as follows: NNC 09-0026, 9.8 microM; CNS 1237, 2.5 microM; SB 201823-A, 4.6 microM; NS 649, 36.7 microM and riluzole, 9.4 microM. In the gerbil model of global cerebral ischaemia the number of viable cells (mean +/- S.E.M.) per 1 mm of the CA1 was 215 +/- 7 (sham operated), 10 +/- 2 (ischaemic control), 44 +/- 15 (NNC 09-0026 30 mg/kg i.p.), 49 +/- 19 (CNS 1237 30 mg/kg i.p.), 11 +/- 2 (SB 201823-A 10 mg/kg i.p.), 17 +/- 4 (NS 649 50 mg/kg i.p.) and 48 +/- 18 (riluzole 10 mg/kg i.p.). Thus NNC 09-0026, CNS 1237 and riluzole provided significant neuroprotection when administered prior to occlusion while SB 201823-A and NS 649 failed to protect. These results indicate that the Ca2+ channel antagonists studied not only inhibited human N-type voltage-dependent Ca2+ channels but were also effective blockers of rat Na+ channels. Both NNC 09-0026 and CNS 1237 showed good activity at both Ca2+ and Na+ channels and this may contribute to the observed neuroprotection.
O'Neill
M J
MJ
Eli Lilly and Company Ltd., Lilly Research Centre, Windlesham, Surrey, United Kingdom. oneill_michael_j@lilly com
Bath
C P
CP
Dell
C P
CP
Hicks
C A
CA
Gilmore
J
J
Ambler
S J
SJ
Ward
M A
MA
Bleakman
D
D
D000818:Animals; D002545:Brain Ischemia / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels / Q000187:drug effects*; D002460:Cell Line; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005849:Gerbillinae; D006146:Guanidines / Q000494:pharmacology; D006801:Humans; D008297:Male; D008978:Mollusk Venoms / Q000494:pharmacology; D018696:Neuroprotective Agents / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D019782:Riluzole / Q000494:pharmacology; D026941:Sodium Channel Blockers; D015222:Sodium Channels / Q000187:drug effects; D013779:Tetrodotoxin / Q000494:pharmacology; D020960:omega-Conotoxins
C096441:CNS 1237; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D018691:Excitatory Amino Acid Antagonists; D006146:Guanidines; D008978:Mollusk Venoms; D018696:Neuroprotective Agents; D010455:Peptides; D010880:Piperidines; D016194:Receptors, N-Methyl-D-Aspartate; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D020960:omega-Conotoxins; C088314:NNC 09-0026; C085883:SB 201823-A; D013779:Tetrodotoxin; D016291:Dizocilpine Maleate; C078452:ziconotide; D019782:Riluzole