Synthetic cannabinoid receptor agonists inhibit the cardiac voltage-gated potassium channel hERG

Synthetic cannabinoid receptor agonists (SCRAs) are 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 K_V11.1) and K_V7.1/KCNE1. We report that the majority of tested SCRAs inhibited hERG, primarily by reducing channel conductance, and some also inhibited K_V7.1/KCNE1. In silico data suggest that SCRAs may use both a known drug binding site in the central cavity of the hERG channel, shared by established hERG blockers like astemizole, and a recently identified side pocket site. Experimental and in silico data suggest SCRA structural features associated with prominent inhibitory effects on hERG, with chemical moieties allowing bond formation and/or the ability to fit into binding sites being important. Structure-activity relationships (SAR) for SCRA effects on hERG, K_V7.1/KCNE1 and the cannabinoid receptor 1 (CB₁) varied, demonstrating the need to assess SCRA effects on multiple potential targets. In conclusion, we found SCRAs to be inhibitors of cardiac voltage-gated potassium channels important for cardiomyocyte repolarization, highlighting the importance of more extensive investigation of SCRAs on cardiac function.