Moving forward, there are three aims for future studies; improve specificity, reduce off-target activity, and improve potency (see Outstanding Questions). Current studies on ML297-related SAR and GiGA1 analog analysis revealed the essential chemical groups on these two molecules. The initial optimization of ML297 has been focused on the modification of the aryl/heteroaryl group while leaving the essential urea linker and N-pyrazole intact. Subsequent studies determined that the substitution of urea linker improved subunit specificity. GiGA1 was developed by varying the number of methyl groups on the phenyl ring of NCATS_2. This small modification surprisingly increased the subunit specificity and potency of GiGA1. Despite the structural similarities between ML297 and GiGA1, the mutagenesis studies performed indicate different binding sites for these molecules. Further high-resolution structural studies of these drugs bound to GIRK1 containing channels will help further elucidate the structural features underlying their activity and selectivity. Moreover, future SAR studies and chemical optimization of the existing templates can be performed to improve the specificity of the drugs as well as targeting heterotetramers, such as GIRK1/GIRK3 or GIRK2/GIRK3, for which there are
