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NEUROPHARMACOLOGY

Hydroxyamide Analogs of Propofol Exhibit State-Dependent Block of Sodium Channels in Hippocampal Neurons: Implications for Anticonvulsant Activity

Departments of Chemistry (P.J.J., Y.W., H.S.E., M.L.B.), Anesthesiology (N.J.H., M.K.P.), Neurology (J.K.), and Neuroscience Graduate Program (N.J.H.), University of Virginia, Charlottesville, Virginia; and Anticonvulsant Drug Development Program, Department of Pharmacology and Toxicology (M.D.S., H.S.W.), University of Utah, Salt Lake City, Utah

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 Mg²⁺/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.

Address correspondence to: Dr. Manoj K. Patel, Department of Anesthesiology, University of Virginia Health Systems, 1 Hospital Drive, Old Medical School, Charlottesville, VA 22908. E-mail: mkp5u{at}virginia.edu