In recent years, a structure-based search of small molecule modulators of GIRK channels derived from ML297 yielded an extensive family of GIRK activators, with variable potency and selectivity (Figure 2A). The N-phenyl substituted pyrazole and the NH moieties of the urea linkage in ML297 appeared to be essential for GIRK activation (Figure 2A) [25]. Therefore, the first efforts focused on structure-activity relationship (SAR) studies and iterative parallel synthesis to generate a myriad of urea-bearing chemical families that behaved identically with regard to GIRK selectivity, activating only GIRK1-containing channels [29, 30]. For example, the N-benzyl pyrazole derivative VU0466551 was a more potent activator of GIRK1/GIRK2 channels (EC50 of 70 nM for VU0466551 vs. 160 nM for ML297), and retained selectivity for GIRK1-containing channels [29, 31].
