In vitro: ICA-069673 is found to be 20-fold selective for KCNQ2/Q3 over KCNQ3/Q5 and has no measurable activity against a panel of cardiac ion channels (IC50 values > 30 μM for hERG, Nav1.5, L type channels, and KCNQ1) as well as no activity on GABA(A) gated channels at 10 μM. ICA-069673 exhibits much stronger effects on KCNQ2 channels, including a large hyperpolarizing shift of the voltage-dependence of activation, an 2-fold enhancement of peak current and pronounced subtype specificity for KCNQ2 over KCNQ3. Based on ICA73 sensitivity of chimeric constructs of the transmembrane segments of KCNQ2 and KCNQ3, this drug appears to interact with the KCNQ2 voltage sensor (S1-S4).
|Cell lines||DSM cells|
|Preparation method||For the first protocol, continuous stimulation of 10-Hz EFS frequency was delivered at 1-minute intervals and a stable baseline and amplitude were reached prior to applying increasing concentrations of ICA-069673 (100 nM–30 µM). In the second EFS protocol, we applied incremental EFS stimulation frequencies (3.5, 5, 7.5, 10, 12.5, 15, 20, 30, 40, and 50 Hz) at 3-minute intervals for a control period, and then again in the presence of a single concentration of ICA-069673 (either 3 or 10 µM).|
|Concentrations||100 nM–30 µM|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Solubility||≥ 34 mg/mL in DMSO|
The Novel KV7.2/KV7.3 Channel Opener ICA-069673 Reveals Subtype-Specific Functional Roles in Guinea Pig Detrusor Smooth Muscle Excitability and Contractility
Aaron Provence, et al. J Pharmacol Exp Ther. 2015 Sep;354(3): 290–301. PMID: 26087697.
Differential activation of vascular smooth muscle Kv7.4, Kv7.5, and Kv7.4/7.5 channels by ML213 and ICA-069673.
Brueggemann LI, et al. Mol Pharmacol. 2014 Sep;86(3):330-41. PMID: 24944189.
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