Targeting acute ischemic stroke with a calcium-sensitive opener of maxi-K potassium channels.
During ischemic stroke, neurons at risk are exposed to pathologically high levels of intracellular calcium (Ca++), initiating a fatal biochemical cascade. To protect these neurons, we have developed openers of large-conductance, Ca++-activated (maxi-K or BK) potassium channels, thereby augmenting an endogenous mechanism for regulating Ca++ entry and membrane potential. The novel fluoro-oxindoles BMS-204352 and racemic compound 1 are potent, effective and uniquely Ca++-sensitive openers of maxi-K channels. In rat models of permanent large-vessel stroke, BMS-204352 provided significant levels of cortical neuroprotection when administered two hours after the onset of occlusion, but had no effects on blood pressure or cerebral blood flow. This novel approach may restrict Ca++ entry in neurons at risk while having minimal side effects.
Gribkoff
V K
VK
Neuroscience Drug Discovery, Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, Connecticut, USA. valentin.gribkoff@bms.com
Starrett
J E
JE
Dworetzky
S I
SI
Hewawasam
P
P
Boissard
C G
CG
Cook
D A
DA
Frantz
S W
SW
Heman
K
K
Hibbard
J R
JR
Huston
K
K
Johnson
G
G
Krishnan
B S
BS
Kinney
G G
GG
Lombardo
L A
LA
Meanwell
N A
NA
Molinoff
P B
PB
Myers
R A
RA
Moon
S L
SL
Ortiz
A
A
Pajor
L
L
Pieschl
R L
RL
Post-Munson
D J
DJ
Signor
L J
LJ
Srinivas
N
N
Taber
M T
MT
Thalody
G
G
Trojnacki
J T
JT
Wiener
H
H
Yeleswaram
K
K
Yeola
S W
SW
D000818:Animals; D001921:Brain / Q000378:metabolism; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D006224:Cricetinae; D004195:Disease Models, Animal; D004285:Dogs; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007211:Indoles / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D051036:Large-Conductance Calcium-Activated Potassium Channels; D008297:Male; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000187:drug effects* / Q000378:metabolism; D024681:Potassium Channels, Calcium-Activated; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D012449:Safety; D020521:Stroke / Q000188:drug therapy* / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects
C424388:BMS204352; D007211:Indoles; D051036:Large-Conductance Calcium-Activated Potassium Channels; D015221:Potassium Channels; D024681:Potassium Channels, Calcium-Activated; D018698:Glutamic Acid; D002118:Calcium