Also based on ML297, Wieting and collaborators generated a novel library of GIRK1/GIRK2 activators that used an acetamide moiety instead of the urea scaffold to improve the selectivity and the pharmacokinetic properties [37]. The new acetamide VU0810464 showed nanomolar potency on GIRK1/GIRK2 (EC50 of 165 nM) and enhanced brain penetration [37, 38]. VU0810464 showed nine times more selectivity for GIRK channels expressed in mice hippocampal neurons than for those in cardiac sino-atrial node cells, indicating a stronger preference for GIRK1/GIRK2 over cardiac GIRK1/GIRK4 heterotetramers [38]. In vivo, 30 mg/kg VU0810464 reduced stress-induced hyperthermia in mice in a GIRK1-dependent manner, although it showed no anxiolytic effect in the EPM test, unlike ML297 [38] (Figure 3). The authors considered that this disparity in the anxiolytic effect of VU0810464 might be caused by its shorter half-life compared to ML297 (≈20 min for VU0810464, ≈40 min for ML297) [38], and by the complementary assessments of anxiety-related behavior provided by these tests. Nevertheless, VU0810464 shows promise for selectively targeting GIRK1/GIRK2 channels, and ongoing studies are using this scaffold to further improve this selectivity profile.
