Based on the potent K<sub>v</sub>7 agonist <b>RL-81</b>, we prepared new lead structures with greatly improved selectivity for K<sub>v</sub>7.2/K<sub>v</sub>7.3 over related potassium channels, i.e., K<sub>v</sub>7.3/K<sub>v</sub>7.5, K<sub>v</sub>7.4, and K<sub>v</sub>7.4/7.5. <b>RL-36</b> and <b>RL-12</b> maintain an agonist EC<sub>2<i>x</i></sub> of ca. 1 μM on K<sub>v</sub>7.2/K<sub>v</sub>7.3 in a high-throughput assay on an automated electrophysiology platform in HEK293 cells but lack activity on K<sub>v</sub>7.3/K<sub>v</sub>7.5, K<sub>v</sub>7.4, and K<sub>v</sub>7.4/7.5, resulting in a selectivity index SI > 10. <b>RL-56</b> is remarkably potent, EC<sub>2<i>x</i></sub> 0.11 ± 0.02 μM, and still shows an SI = 2.5. We also identified analogues with significant selectivity for K<sub>v</sub>7.4/K<sub>v</sub>7.5 over K<sub>v</sub>7.2/K<sub>v</sub>7.3. The extensive use of fluorine in iterative core structure modifications highlights the versatility of these substituents, including F, CF<sub>3</sub>, and SF<sub>5</sub>, to span orders of magnitude of potency and selectivity in medicinal chemistry lead optimizations.