Although ML297 was discovered with a GIRK-specific screening assay, it exhibits some modest off-target activity. ML297 was found to inhibit the hERG potassium channel (KV11.1), albeit at relatively high concentrations (IC50 ≈ 10 μM) [25]. In a radioligand binding assay, ML297 at 10 μM displayed modest activity on 5-HT2b, sigma σ1, and GABAA receptors [25]. Importantly, whole-cell electrophysiology on HEK293 cells expressing GABAA receptors showed no activation with ML297 [25]. ML297 exhibited modest (~3x’s) preference for activating neuronal GIRK1/GIRK2 over cardiac GIRK1/GIRK4 channels, which could produce undesired cardiovascular effects, but had no effect on GIRK2 homotetramers or Kir2.1 channels.
