Hydroxyamide Analogs of Propofol Exhibit State-Dependent Block of Sodium Channels in Hippocampal Neurons: Implications for Anticonvulsant Activity
Although propofol is most commonly known for its general anesthetic properties, at subanesthetic doses, propofol has been effectively used to suppress seizures during refractory status epilepticus, a mechanism, in part, attributed to the inhibition of neuronal sodium channels. In this study, we have...
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Published in | The Journal of pharmacology and experimental therapeutics Vol. 320; no. 2; pp. 828 - 836 |
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Main Authors | , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
American Society for Pharmacology and Experimental Therapeutics
01.02.2007
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Subjects | |
Online Access | Get full text |
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Summary: | Although propofol is most commonly known for its general anesthetic properties, at subanesthetic doses, propofol has been
effectively used to suppress seizures during refractory status epilepticus, a mechanism, in part, attributed to the inhibition
of neuronal sodium channels. In this study, we have designed and synthesized two novel analogs of propofol, HS245 [2-(3-ethyl-4-hydroxy-5-isopropyl-phenyl)-3,3,3-trifluoro-2-hydroxy-propionamide]
and HS357 [2-hydroxy-8-(4-hydroxy-3,5-diisopropyl-phenyl)-2-trifluoromethyl-octanoic acid amide], and determined their effects
on sodium currents recorded from cultured hippocampal neurons. HS357 had greater affinity for the inactivated state of the
sodium channel than propofol and HS245 (0.22 versus 0.74 and 1.2 μM, respectively) and exhibited the greatest ratio of affinity
for the resting over the inactivated state. HS357 also demonstrated greater use-dependent block and delayed recovery from
inactivation in comparison with propofol and HS245. Under current-clamp conditions, action potentials from hippocampal CA1
neurons in slices were evoked by current injection, or following perfusion with a zero Mg 2+ /7 mM K + artificial cerebrospinal fluid solution. Propofol and HS357 reduced the number of current-induced action potentials; however,
HS357 caused a greater reduction in the number of spontaneous action potentials. Consistent with these electrophysiology studies,
propofol and HS357 protected mice against acute seizures in the 6-Hz (22-mA) partial psychomotor model. Efficacious doses
of propofol were associated with an impairment of motor coordination as assessed in the rotorod toxicity assay. In contrast,
HS357 demonstrated a 2-fold greater protective index than propofol. Thus, propofol analogs represent an important structural
class from which not only effective, but also safer, anti-convulsants may be developed. |
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ISSN: | 0022-3565 1521-0103 |
DOI: | 10.1124/jpet.106.111542 |