Resin-acid derivatives as potent electrostatic openers of voltage-gated K channels and suppressors of neuronal excitability

Voltage-gated ion channels generate cellular excitability, cause diseases when mutated, and act as drug targets in hyperexcitability diseases, such as epilepsy, cardiac arrhythmia and pain. Unfortunately, many patients do not satisfactorily respond to the present-day drugs. We found that the naturally occurring resin acid dehydroabietic acid (DHAA) is a potent opener of a voltage-gated K channel and thereby a potential suppressor of cellular excitability. DHAA acts via a non-traditional mechanism, by electrostatically activating the voltage-sensor domain, rather than directly targeting the ion-conducting pore domain. By systematic iterative modifications of DHAA we synthesized 71 derivatives and found 32 compounds more potent than DHAA. The most potent compound, Compound 77, is 240 times more efficient than DHAA in opening a K channel. This and other potent compounds reduced excitability in dorsal root ganglion neurons, suggesting that resin-acid derivatives can become the first members of a new family of drugs with the potential for treatment of hyperexcitability diseases.


Synthesis of compound 22
Supplementary Scheme 11. Synthesis of compound 22.
Step 1. Amination The reaction mixture of DHAA (400.0 mg, 1.331 mMol) and 183 uL 65% HNO3 (167.8, 1.663 mMol) in 8.0 mL Ac2O was stirred at rt overnight, it's fully conversed according to crude HNMR, concentrated to give a raw product for next step without further purification.

Step2 Chlorination
The reaction mixture of 80 (153.0 mg, 0.485 mMol), N-chlorosuccinimide (66.1 mg, 0.495 mMol) in 2 mL DMF was heated under microwave irradiation at 75°C for 30 min, then purified directly on silica gel without concentration or extraction with EtOAc/n-heptane (30:70 to 50:50) three times to give product 81 (44.0 mg, 26% yield), containing small amount of impurities, which was difficult to be removed. The product was then used without further purification in next step.

Synthesis of compounds 25 and 47
Supplementary Scheme 9. Synthesis of compounds 25 and 47.

Synthesis of compounds 26 and 48
Supplementary Scheme 10. Synthesis of compounds 26 and 48.

Synthesis of compound 35
Supplementary Scheme 6. Synthesis of compound 35.