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LMR-101, a novel derivative of propofol, exhibits potent anticonvulsant effects and possibly interacts with a novel target on γ-aminobutyric acid type A receptors

Yi Zhao,Long An,Shupan Guo,Xiaoxing Huang,Huajie Tian,Li Liu,Tao Chen,Xun Sun,Qibing Mei,Rutao Wang

Objective LMR-101 is a bisphenol derivative of propofol, a short-acting general anesthetic, which is also used to manage status epilepticus (SE). We evaluated the sedative and anticonvulsant effects of LMR-101 to discover its potential to manage epilepsy and SE in the clinic. Methods Comparative studies between LMR-101 and propofol were performed in mice to elucidate an appropriate dose range for LMR-101 that produced anticonvulsant effects without significant sedation. Then, the anticonvulsive efficacy for LMR-101 was evaluated using seizure models induced by pentylenetetrazol and (+)-bicuculline. The ability of LMR-101 to inhibit SE was assessed using a rat model of SE induced by pilocarpine. Radioligand binding assay profiles for LMR-101 were performed to evaluate the potential mechanisms of action underlying its anticonvulsant properties. Results In the mouse study, LMR-101 exhibited greater anticonvulsant and lesser sedative effect compared with propofol. LMR-101 completely inhibited pentylenetetrazol-induced seizures at a dose of 50 mg/kg and exhibited heavy sedation at 300 mg/kg. Propofol anesthetized all mice and only decreased the seizure rate at 25 mg/kg. LMR-101 also suppressed seizure behaviors evoked by (+)-bicuculline in mice in a dose-dependent manner. In the pilocarpine-induced SE model, LMR-101 significantly decreased the maximum seizure score and seizure duration in a dose-dependent manner. The median effective dose for LMR-101 was 14.30 mg/kg and 121.87 mg/kg to prevent and inhibit sustained SE, respectively. In binding assays, LMR-101 primarily inhibited tert -[ 35 S] butylbicyclophosphorothionate binding to γ-aminobutyric acid type A (GABA A ) receptors (half-maximal inhibitory concentration = 2.06 μmol·L –1 ), but it did not affect [ 3 H] flunitrazepam or [ 3 H] muscimol binding. Significance It is anticipated that LMR-101 might play an essential role in the clinical management of epilepsy and SE. LMR-101 also might bind to a novel target site on the GABA A receptor that is different from existing antiepileptic drugs. Further study of the mechanisms of action of LMR-101 would be of considerable value in the search for new active drug sites on GABA A receptors.