Characterisation of SB-221420-A - a neuronal Ca(2+) and Na(+) channel antagonist in experimental models of stroke.
For progression to clinical trials in stroke, putative neuroprotective compounds should show robust efficacy post-ischaemia in several experimental models of stroke. This paper describes the characterisation of (+)(1S, 2R)-cis-1-[4-(1-methyl-1-phenylethyl)phenoxy]-2-methylamino indane hydrochloride (SB-221420-A), a Ca(2+) and Na(+) channel antagonist. SB-221420-A inhibited (IC(50)=2.2 microM) N-type voltage-operated Ca(2+) channel currents in cultured superior cervical ganglion neurons, which were pretreated with 10 microM nimodipine to block L-type voltage-operated Ca(2+) channel currents. In dorsal root ganglion neurons pretreated with 1 microM omega-conotoxin GVIA to block N-type voltage-operated Ca(2+) channel currents, SB-221420-A inhibited the residual Ca(2+) current with an IC(50) of 7 microM. SB-221420-A also inhibited Na(+) currents in dorsal root ganglion neurons with an IC(50) of 8 microM. In rats, the pharmacokinetic profile of SB-221420-A shows that it has a half-life of 6.4 h, a high volume of distribution, is highly brain penetrating, and has no persistent metabolites. Following bilateral carotid artery occlusion in gerbils, SB-221420-A significantly reduced the level of ischaemia-induced hyperlocomotor activity and the extent of hippocampal CA1 cell loss compared to the ischaemic vehicle-treated group. SB-221420-A was also effective in focal models of ischaemia. In the mouse permanent middle cerebral artery occlusion model, SB-221420-A (10 mg/kg) administered intravenously, post-ischaemia significantly (P<0.05) reduced lesion volume compared to the ischaemic vehicle-treated group. In the normotensive rat permanent middle cerebral artery occlusion model, SB-221420-A (10 mg/kg) administered intravenously over 1 h, beginning 30 min postmiddle cerebral artery occlusion, significantly (P<0.05) reduced lesion volume from 291+/-16 to 153+/-30 mm(3), compared to ischaemic vehicle-treated controls when measured 24 h postmiddle cerebral artery occlusion. Efficacy was maintained when the same total dose of SB-221420-A was infused over a 6-h period, beginning 30 min postmiddle cerebral artery occlusion. SB-221420-A also significantly (P<0.05) reduced lesion volume following transient middle cerebral artery occlusion in normotensive rats and permanent middle cerebral artery occlusion in spontaneously hypertensive rats (SHR). Investigation of the side effect profile using the Irwin screen in mice revealed that, at neuroprotective doses, there were no overt behavioural or cardiovascular changes. These data demonstrate that robust neuroprotection can be seen post-ischaemia with SB-221420-A in both global and focal ischaemia with no adverse effects at neuroprotective doses, and indicate the potential utility of a mixed cation blocker to improve outcome in cerebral ischaemia.
Campbell
C A
CA
Neuroscience Research, SmithKline Beecham Pharmaceuticals, New Frontiers Science Park, Third Avenue, Harlow, CM19 5AW, Essex, UK. colin_a_campbell@sbphrd.com
Barone
F C
FC
Benham
C D
CD
Hadingham
S J
SJ
Harries
M H
MH
Harling
J D
JD
Hills
J M
JM
Lewis
V A
VA
Mackay
K B
KB
Orlek
B S
BS
White
R F
RF
Parsons
A A
AA
Hunter
A J
AJ
D000758:Anesthesia; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000187:drug effects / Q000473:pathology; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D016893:Carotid Stenosis / Q000503:physiopathology / Q000517:prevention & control; D002478:Cells, Cultured; D003243:Consciousness; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D005849:Gerbillinae; D006439:Hemodynamics / Q000187:drug effects; D006973:Hypertension / Q000503:physiopathology; D007189:Indans / Q000493:pharmacokinetics / Q000494:pharmacology*; D020244:Infarction, Middle Cerebral Artery / Q000473:pathology / Q000517:prevention & control; D002546:Ischemic Attack, Transient / Q000503:physiopathology / Q000517:prevention & control; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008657:Metabolic Clearance Rate; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D009475:Neurons, Afferent / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D017207:Rats, Sprague-Dawley; D026941:Sodium Channel Blockers; D020521:Stroke / Q000503:physiopathology / Q000517:prevention & control*; D014018:Tissue Distribution
D002121:Calcium Channel Blockers; D007189:Indans; D018696:Neuroprotective Agents; C414355:SB 221420-A; D026941:Sodium Channel Blockers