Recently, Xu and collaborators carried out a chemical optimization of ML297 and generated GAT1508, a bromo-substituted thiophene derivative that conserves the urea and the N-phenyl-pyrazole moieties, and improved the potency and selectivity for GIRK1/GIRK2 channels [40]. In electrophysiological recordings from HEK293 cells expressing either GIRK1/GIRK2 or GIRK1/GIRK4, GAT1508 activated GIRK1/GIRK2 more than ML297 (EC50 of 75 nM versus 110 nM for ML297) and showed little activation of GIRK1/GIRK4. Computational modeling and mutagenesis studies performed by Xu and collaborators [40] suggested that GAT1508 binds to the same residues in GIRK1 as ML297 [26] (Figure 1). Importantly, GAT1508 did not affect cardiovascular parameters in mice, including the atrial action potential duration, consistent with its lack of activity on cardiac GIRK1/GIRK4 channels [40]. GAT1508 perfusion increased barium-sensitive outward currents in basolateral amygdala neurons in brain slices (Table 1), and potentiated the effects of baclofen, supporting the action of GAT1508 on GIRK1/GIRK2 channels [40]. Given the role that the amygdala plays in fear conditioning, Xu and collaborators evaluated GAT1508 in rats using a Pavlovian conditioned fear paradigm, a preclinical model of post-traumatic stress disorder
