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Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels play a critical role in controlling pacemaker activity in both heart and nervous system.Developing HCN channel inhibitors has been proposed to be an important strategy for the treatment of pain,heart failure,arrhythmias,and epilepsy.One HCN channel inhibitor,ivabradine,has been clinically approved for the treatment of angina pectoris and heart failure.In this study,we designed and synthesized eight alkanol amine derivatives,and assessed their effects on HCN channels expressed in COS7 cells using a whole-cell patch clamp method.Among them,compound 4e displayed the most potent inhibitory activity with an IC50 of 2.9 ± 1.2 μM at-120 mV on HCN2 channel expressed in COS7 cells.Further analysis revealed that application of compound 4e (10 μM) caused a slowing of activation and a hyperpolarizing shift (Δ1/2 =-30.2 ± 2.9 mV,n =5) in the voltage dependence of HCN2 channel activation.The inhibitory effect of compound 4e on HCN1 andHCN4 channel expressed in COS7 cells was less potent with IC50 of 17.2 ± 1.3 and 7.3 ± 1.2 μM,respectively.Besides,we showed that application of compound 4e (10 μM) inhibited Ih and action potential firing in acutely dissociated mouse small dorsal root ganglion neurons.Our study provides a new strategy for the design and development of potent HCN channel inhibitors.