Comparative molecular field analysis and synthetic validation of a hydroxyamide-propofol binding and functional block of neuronal voltage-dependent sodium channels.

摘要: Abstract Voltage gated sodium channels represent an important therapeutic target for a number of neurological disorders including epilepsy. Unfortunately, medicinal chemistry strategies discovering new classes antagonist trans-membrane ion have been limited to mostly broad screening compound arrays. We developed channel based on propofol scaffold using the ligand strategy comparative molecular field analysis (CoMFA). The resulting CoMFA model was correlated and validated provide insights into design antagonists prioritize synthesis these structural analogs (compounds 4 5 ) that satisfied steric electrostatic model. Compounds were evaluated [ 3 H]-batrachotoxinin-A-20-α-benzoate ([ H]-BTX-B) displacement yielding IC 50 ’s 22 5.7 μM, respectively. further examined potency two compounds inhibit neuronal currents recorded from cultured hippocampal neurons. At concentration 50 μM, tonically inhibited by 59 ± 7.8% ( n  = 5) 70 ± 7.5%  = 7), This clearly demonstrates functionally antagonize native currents. In summary, we shown can be effectively used discover antagonists.