Discovery of a potent, Kv7.3-selective potassium channel opener from a Polynesian traditional botanical anticonvulsant

The voltage-gated potassium (Kv) channel formed by Kv7.2/3
(KCNQ2/3) heteromers is a major target for anticonvulsant drug
development. Here, we screened 1,444 extracts primarily from
plants collected in California and the US Virgin Islands, for
their ability to activate Kv7.2/3 but not inhibit Kv1.3, to
select against tannic acid being the active component. We
validated the 7 strongest hits, identified Thespesia populnea
(miro, milo, portia tree) as the most promising, then discovered
its primary active metabolite to be gentisic acid (GA). GA highly
potently activated Kv7.2/3 (EC50, 2.8 nM). GA is, uniquely,
100% selective for Kv7.3 versus other Kv7 homomers; it requires
S5 residue Kv7.3-W265 for Kv7.2/3 activation, and it ameliorates
pentylenetetrazole-induced seizures in mice. Also an active
aspirin metabolite, GA provides a molecular rationale for the use
of T. populnea as an anticonvulsant in Polynesian indigenous
medicine and presents novel pharmacological prospects for potent,
isoform-selective, therapeutic Kv7 channel activation.