Loss of function of voltage-gated
potassium (Kv) channels is linked to a range of lethal or debilitating
channelopathies. New pharmacological approaches are warranted to
isoform-selectively activate specific Kv channels. One example is KCNA1
Potassium Voltage-Gated Channel Subfamily A Member 1 (KCNA1) (Kv1.1), an archetypal Shaker-type Kv channel, in which loss-of-function mutations cause
episodic ataxia type 1 (EA1). EA1 causes constant myokomia and episodic bouts of
ataxia and may associate with
epilepsy and other disorders. We previously found that the inhibitory
neurotransmitter γ-
aminobutyric acid and modified versions of
glycine directly activate Kv channels within the KCNQ subfamily, a characteristic favored by strong negative electrostatic surface potential near the
neurotransmitter carbonyl group. Here, we report that adjusting the number and positioning of
fluorine atoms within the fluorophenyl ring of
glycine derivatives produces
isoform-selective KCNA1 channel openers that are inactive against KCNQ2/3 channels, or even KCNA2, the closest relative of KCNA1. The findings refine our understanding of the molecular basis for KCNQ versus KCNA1 activation and
isoform selectivity and constitute, to our knowledge, the first reported
isoform-selective KCNA1 opener. SIGNIFICANCE STATEMENT: Inherited loss-of-function gene sequence variants in KCNA1, which encodes the KCNA1 (Kv1.1)
voltage-gated potassium channel, cause
episodic ataxia type 1 (EA1), a
movement disorder also linked to
epilepsy and developmental delay. We have discovered several
isoform-specific KCNA1-activating small molecules, addressing a notable gap in the field and providing possible lead compounds and a novel chemical space for the development of potential future therapeutic drugs for EA1.