The Anticonvulsant Effects of Propofol and a Propofol Analog, 2,6-Diisopropyl-4-(1-Hydroxy-2,2,2-Trifluoroethyl)Phenol, in a 6 Hz Partial Seizure Model

Propofol is a general anesthetic having good anticonvulsant properties, but is limited in antiseizure use because of its potent anesthetic/sedative properties. It is proposed that substitution of the propofol molecule in the para position may yield compounds having less toxicity, yet possessing anticonvulsant properties because of retention of the 2,6-diisopropylphenol configuration. Reported herein is the synthesis of a para-substituted analog of propofol, 2,6-diisopropyl-4-(1-hydroxy-2,2,2-trifluoroethyl)phenol (MB003), and a similar analog of 2,6-di-sec-butylphenol (MB050), and their comparative anticonvulsant effects in National Institute of Neurological Disorders and Stroke screening models. MB003 and MB050 were synthesized by the reaction of propofol or 2,6-di-sec-butylphenol, respectively, with trifluoroacetaldehyde ethyl hemiacetal in the presence of catalytic amounts of K(2)CO(3). Compounds were purified to >98% purity. Propofol, MB003, 2,6-di-sec-butylphenol, and MB050 were screened for protective effects by the National Institute of Neurological Disorders and Stroke Anticonvulsant Screening Program in the mouse maximal electroshock, subcutaneous metrazol, and 6 Hz (32 mA) partial seizure models. All compounds were administered by i.p. injection. The toxicity of each compound was assessed by the ability of the animals to stay on a Rotorod after dosing. Propofol, MB003, and MB050 were found to be most protective in the 6 Hz model with lesser protective effects in the mouse maximal electroshock and subcutaneous metrazol models. In the 6 Hz model, propofol yielded a 50% effective dose of 32.8 mg/kg; MB003, 38.4 mg/kg; and MB050, 74.0 mg/kg. Propofol, and to a greater degree, 2,6-di-sec-butylphenol, exhibited high toxicity. The corresponding 2,6-dimethylphenol analog to MB003 and MB050, 2,6-dimethyl-4-(1-hydroxy-2,2,2-trifluoroethyl)phenol, was not protective in the 6 Hz model and exhibited no toxicity at any dose tested. These results show that the anesthetics propofol and 2,6-di-sec-butylphenol may be substituted in the para position with a 1-hydroxy-2,2,2-trifluoroethyl moiety and the resulting molecules have anticonvulsant activity in the 6 Hz model while exhibiting less toxicity (ataxia) than the parent 2,6-dialkylphenols. The effectiveness of propofol, MB003, 2,6-di-sec-butylphenol, and MB050 and the ineffectiveness of 2,6-dimethyl-4-(1-hydroxy-2,2,2-trifluoroethyl)phenol, in the 6 Hz model shows that the 2,6-diisopropyl or 2,6-di-sec-butyl phe