pan-HCN-IN-1 is a potent HCN ion channel inhibitor with IC50 values of 58 nM, 522 nM, 58 nM, and 58 nM against HCN1, HCN2, HCN3, and HCN4, respectively. pan-HCN-IN-1 exerts voltage-dependent but not use-dependent inhibition, potently inhibits channels in the closed state, and significantly slows the activation time constant of HCN1 currents. pan-HCN-IN-1 can be used for the research of cognitive dysfunction [1].
In Vivo, pan-HCN-IN-1 (Compound J&J12e) (3-10 mg/kg; i.p.; single administration; 30 min) induces severe dose-limiting side effects in naive rats[1]. pan-HCN-IN-1 (0.8-10 mg/kg; i.p.; single administration; 30 min) exerts effects of failing to improve working memory and even exacerbating the deterioration of cognitive performance at the highest dose in both normal rats and rats with MK-801 -induced injury[1]. pan-HCN-IN-1 (2.5 mg/kg; i.p.; single administration; monitored for approximately 20 h) exerts a significant heart rate-lowering effect in healthy rats implanted with wireless telemetry devices[1].
In Vitro, Pan-HCN-IN-1 (Compound J&J12e) (14.6 nM - 30 µM; 10 min) potently and non-selectively inhibits HCN1, HCN2, and HCN4 channels expressed in HEK293 cells. It exhibits voltage-dependent inhibitory properties, rapid onset of action, and slows the activation kinetics of HCN1, with an IC50 of 58 nM against HCN1 channels[1]. pan-HCN-IN-1 inhibits HCN1 currents in HEK cells overexpressing HCN1, with voltage-dependent potency that reaches the highest level at -80 mV (IC50 = 25 nM) and the lowest level at -120 mV (IC50 = 148 nM)[1]. pan-HCN-IN-1 exhibits detectable metabolic clearance in human and rat microsomes and hepatocytes, shows weak P-gp-mediated efflux, has low plasma protein binding in rats, and potently inhibits hERG channels (IC20 = 0.04 μM)[1]. pan-HCN-IN-1 potently inhibits rHCN1 (IC50 = 9 nM) and modulates the activation kinetics of HCN channels in transiently transfected HEK cells, with a faster onset of block for rHCN1 than for hHCN1[1]. pan-HCN-IN-1 (0.02 µM) increases the tau value of HCN1 channel activation in HEK cells overexpressing HCN1[1]. Pan-HCN-IN-1 (0.03 µM-10 µM; 5 min per concentration) alters the electrophysiological properties of human induced pluripotent stem cell-derived atrial-like cardiomyocytes, prolongs the beating cycle and changes the peak potential amplitude[1]. pan-HCN-IN-1 alters the electrophysiological function of spontaneously beating atrial-like hIPS cardiomyocytes, prolongs the field potential duration, and simultaneously reduces the beating frequency and spike potential amplitude[1].
References:
[1]. Harde E, et al. Selective and brain-penetrant HCN1 inhibitors reveal links between synaptic integration, cortical function, and working memory. Cell chemical biology. 2024 Mar 21;31(3):577-592.e23.
In Vivo, pan-HCN-IN-1 (Compound J&J12e) (3-10 mg/kg; i.p.; single administration; 30 min) induces severe dose-limiting side effects in naive rats[1]. pan-HCN-IN-1 (0.8-10 mg/kg; i.p.; single administration; 30 min) exerts effects of failing to improve working memory and even exacerbating the deterioration of cognitive performance at the highest dose in both normal rats and rats with MK-801 -induced injury[1]. pan-HCN-IN-1 (2.5 mg/kg; i.p.; single administration; monitored for approximately 20 h) exerts a significant heart rate-lowering effect in healthy rats implanted with wireless telemetry devices[1].
In Vitro, Pan-HCN-IN-1 (Compound J&J12e) (14.6 nM - 30 µM; 10 min) potently and non-selectively inhibits HCN1, HCN2, and HCN4 channels expressed in HEK293 cells. It exhibits voltage-dependent inhibitory properties, rapid onset of action, and slows the activation kinetics of HCN1, with an IC50 of 58 nM against HCN1 channels[1]. pan-HCN-IN-1 inhibits HCN1 currents in HEK cells overexpressing HCN1, with voltage-dependent potency that reaches the highest level at -80 mV (IC50 = 25 nM) and the lowest level at -120 mV (IC50 = 148 nM)[1]. pan-HCN-IN-1 exhibits detectable metabolic clearance in human and rat microsomes and hepatocytes, shows weak P-gp-mediated efflux, has low plasma protein binding in rats, and potently inhibits hERG channels (IC20 = 0.04 μM)[1]. pan-HCN-IN-1 potently inhibits rHCN1 (IC50 = 9 nM) and modulates the activation kinetics of HCN channels in transiently transfected HEK cells, with a faster onset of block for rHCN1 than for hHCN1[1]. pan-HCN-IN-1 (0.02 µM) increases the tau value of HCN1 channel activation in HEK cells overexpressing HCN1[1]. Pan-HCN-IN-1 (0.03 µM-10 µM; 5 min per concentration) alters the electrophysiological properties of human induced pluripotent stem cell-derived atrial-like cardiomyocytes, prolongs the beating cycle and changes the peak potential amplitude[1]. pan-HCN-IN-1 alters the electrophysiological function of spontaneously beating atrial-like hIPS cardiomyocytes, prolongs the field potential duration, and simultaneously reduces the beating frequency and spike potential amplitude[1].
References:
[1]. Harde E, et al. Selective and brain-penetrant HCN1 inhibitors reveal links between synaptic integration, cortical function, and working memory. Cell chemical biology. 2024 Mar 21;31(3):577-592.e23.