Page 8 - CBAC Newsletter 2016
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Retigabine also relieves behaviors related to anxiety Although RTG can prevent the excessive firing
(103,104), and other studies have shown pain-reliever associated with seizures and the spontaneous firing that
effects of retigabine in several animal models causes tinnitus (95,99), it has many adverse side
(105-107). Still more studies have reported that RTG is a effects, such as urinary retention, skin discoloration,
broad-spectrum agent for treating epilepsy and seizure and retinal disorders (124). These undesired side
in vivo, including chemically and electrically induced effects limit the uses of retigabine. Most of the
seizures in almost every animal seizure model undesired effects of retigabine arise because of the
(108,109). As an example, rats with complex partial general lack of selectivity of KCNQ channels. Retigabine
seizures have been treated with RTG, which is effective for many forms of epilepsy because of its
dose-dependently increases the threshold current for action on KCNQ2 and KCNQ3 channels, while its
induction, and decreases the seizure severity, peak du- potentiation effect on KCNQ4 and KCNQ5 channels in
ration, total duration, and changes after discharge (110). smooth muscles, as an example, reduces contractile
It has also an agonistic action on GABAA responses through membrane hyperpolarization (2,125).
receptors, the major inhibitory channels in the central Agents that will selectively activate only KCNQ2 and
nervous system, which are associated with epilepsy KCNQ3 channels are urgently needed to treat neuronal
disorders (108,110,111). hyperexcitability disorders related to M-current
RTG has shown interesting pharmacological action in channels, such as epilepsy, migraine, and chronic
potentiating KCNQ2/KCNQ3 potassium channels (Table pain. Retigabine is currently the only globally approved
1). RTG’s effects on the heterotetramer KCNQ2/KCNQ3 voltage-gated potassium channels opener (126). For
channels include enhanced activation rate, slowed attempts to discover analogues with better potency and
deactivation rate and leftward shifting of the activation specificity it is extremely important to understand the
voltage curve by 30 mV (100,101,112). These effects complex mechanism of channel activation by RTG.
cause neuronal hyperpolarization both during membrane 2. SF0034
resting and after an action potential (100). The binding SF0034 was discovered by adding a fluorine atom to
with RTG could theoretically decrease the required retigabine to achieve a more potent and selective
energy for channel activation because opening the molecule acting on KCNQ channels (Fig.2) (127).
channel will require a lesser depolarization. SF0034 is selective for KCNQ2/3 channels, and can
(70,100,113-116). manage seizure and reduce the number of side effects
A structural analog to the centrally acting analgesic (Table 1) (127). SF0031 has displayed several times
flupirtine, RTG activates KCNQ channels by binding to better potency than retigabine with heteromeric
TM5 and TM6 regions. The amino acid sequences of KCNQ2/3 channels in HEK293T cells. It has also been
TM5 and TM6 segments are more than 90% conserved shown that SF0034 shifts the voltage dependence of
in KCNQ2 and KCNQ3, and RTG similarly affects the KCNQ2/3 channels to more negative voltages. Unlike
KCNQ2 and KCNQ3 homomeric channels (117). The retigabine, it does not shift the voltage dependence of
TM5 and TM6 domains of KCNQ1 and KCNQ2 subunits homotetramer KCNQ4 or KCNQ5 channels (127).
differ by only 13 amino acids. A study has shown that Interestingly, the lack of effect on KCNQ4 channels
the sensitivity of RTG to KCNQ2 channels was lost when makes SF0034 an important drug candidate, because
tryptophan 236 in TM5 was mutated to the KCNQ4 is the main potassium channel that regulates
corresponding leucine 246 in the KCNQ1 subunit. the contractility of the smooth muscles in the bladder
KCNQ2 subunits with a TM6 sequence of KCNQ1 (2,125). Retigabine, but not SF0034, creates a major
subunits make channels insensitive to RTG, however, side effect by activating KCNQ4 in the bladder leading
the channels are still functional (101). These findings to membrane hyperpolarization, loss of contractility, and
demonstrated that the conserved tryptophan residue in urinary retention. Persistent deafness can also occur
KCNQ2–5 channels, but not KCNQ1, is essential for when KCNQ4 functions are impaired (128). Also, KCNQ4
retigabine sensitivity to M-current (117,118). The and -5 subunits are expressed in skeletal muscles,
interesting mechanism of retigabine action has SF0034, which has no effect on either KCNQ4 or -5
attracted much attention to discovery and screening of channels, does not have the side effects of retigabine
derivatives for the new class of drugs and treatments. (2,129,130). The higher potency and selectivity of
The discovery of ligands with better subunit selectivity SF0034 could avoid many of retigabine’s toxicities,
will improve ligand effectiveness in treating different making it a better choice as a KCNQ2/3 channel
disorders with minimal side effects (17,98,119-123). opener.
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