A broad set of synthetic cannabinoid receptor agonists inhibit the cardiac voltage-gated potassium channel hERG

Synthetic cannabinoid receptor agonists (SCRAs) is a large group of structurally diverse designer drugs (analogues of controlled substances) associated with intense and sometimes fatal intoxication. Cardiac symptoms including tachycardia and arrhythmia are common consequences of SCRA consumption. However, little is known about the mechanisms through which SCRAs may perturb cardiac rhythm. Here we used electrophysiological techniques to screen 36 SCRAs on two ion channels responsible for cardiomyocyte repolarization, hERG (also called KV11.1) and KV7.1/KCNE1. We report that the majority of tested SCRAs inhibited hERG, primarily by reducing channel conductance, and some also inhibited KV7.1/KCNE1. In silico data suggests that SCRAs use a known drug binding site in the pore of the hERG channel, shared by established hERG blockers like astemizole, where a planar SCRA molecule lays perpendicular to the ion conducting pathway. Experimental and in silico data identify SCRA structural features associated with prominent inhibitory effects on hERG, with chemical moieties allowing bond formation and/or the ability to fit into the vestibule being important. Structure-activity-relationships for SCRA effects on hERG, KV7.1/KCNE1 and the cannabinoid receptor 1 (CB1) varied, demonstrating the importance of assessing SCRA effects on multiple potential targets. In conclusion, we found SCRAs to be inhibitors of cardiac voltage-gated potassium channels important for cardiomyocyte repolarization. These results offer mechanistic insight into potentially detrimental SCRA effects on the heart and highlight the urgency of more extensive investigation of SCRAs on cardiac function.