Design, Synthesis And Structure-Activity Relationship Studies Of KCNQ2 Activators

KCNQ channel belongs to voltage-gated potassium channel, characterised by a slow activation and deactivation current, it can regulate the normal metabolism process. KCNQ genes encode five KCNQ channel subunits (KCNQ1-5), which are widely expressed in cardiac, nervous system and smooth muscle etc. Mutations in the KCNQ gene cause dysfunction in KCNQ channel, which leads to LQT1, DFNA2, epilepsy, pain and cognitive impairment etc. Therofore KCNQ channel can be a therapeutic target to treat the related diseases.In 2011, FDA approve Retigabine for the adjunctive treatment of partial-onset seizures in patients with further promoting the research progress of KCNQ channel modulators. At present, Retigabine is the only drug for targeting KCNQ2/3 channel to treat seizures on the market. But it has many adverse effects, such as somnolence, confusional state, memory impairment, balance disorder and retina dyspigmentation etc, particularly it leads to the skin and retina dyspigmentation, which may cause the potential risk of irreversible vision loss. Because Retigabine can function in central nervous system and peripheral organs smooth muscle (such as the bladder), we must reaserch the selective KCNQ2 or KCNQ3 channel activitors as antiepileptic drug.We identify some compounds which have the struture of 1-phenyl-2-thiol-1H-imidazole, they can excite KCNQ2 channel by High-throughput screening. We modify the structure’s A (phenyl), B (amide) and C (ortho-substituted carbonyl) part. All of the three partion can affect the activity of the compound. When part A is replaced by 3-CF3PI1, the avtivity of compounds is obviously increased; When part B is replaced by (1R,2R,4S)-exo-bicyclo[2.2.1]heptane or azocane, the compound make the electric current of KCNQ2 channel enhanced violently; When part C is replaced by ethyl or isopropyl, it can improve the activity as well. Eventualy, we obtain some compound with good activity, particular the compound L32(LN-395A) and L39(LN-397A), which has the highest activity among all the compounds, with better current enhancing effect and the left-shifting effects on half-activation potentials. We summarize the relationship between strucure and activity, which give some scientific bases and support for the further structure optimization and research.