1. The effects of the antidiabetic agent englitazone and the anorectic drug ciclazindol on ATP-sensitive K+ (KATP) channels activated by diazoxide and leptin were examined in the CRI-G1 insulin-secreting cell line using whole cell and single channel recording techniques. 2. In whole cell current clamp mode, the hyperglycaemic agent diazoxide (200 µM) and the ob gene product leptin (10 nM) hyperpolarised CRI-G1 cells by activation of KATP currents. KATP currents activated by either agent were inhibited by tolbutamide, with an IC50 for leptin-activated currents of 9.0 µM. 3. Application of englitazone produced a concentration-dependent inhibition of KATP currents activated by diazoxide (200 µM) with an IC50 value of 7.7 µM and a Hill coefficient of 0.87. In inside-out patches englitazone (30 µM) also inhibited KATP channel currents activated by diazoxide by 90.8±4.1%. 4. In contrast, englitazone (1-30 µM) failed to inhibit KATP channels activated by leptin, although higher concentrations (> 30 µM) did inhibit leptin actions. The englitazone concentration inhibition curve in the presence of leptin resulted in an IC50 value and Hill coefficient of 52 µM and 3.2, respectively. Similarly, in inside-out patches englitazone (30 µM) failed to inhibit the activity of KATP channels in the presence of leptin. 5. Ciclazindol also inhibited KATP currents activated by diazoxide (200 µM) in a concentration-dependent manner, with an IC50 and Hill coefficient of 127 nM and 0.33, respectively. Furthermore, application of ciclazindol (1 µM) to the intracellular surface of inside-out patches inhibited KATP channel currents activated by diazoxide (200 µM) by 86.6±8.1%. 6. However, ciclazindol was much less effective at inhibiting KATP currents activated by leptin (10 nM). Ciclazindol (0.1-10 µM) had no effect on K(ATP) currents activated by leptin, whereas higher concentrations (> 10 µM) did cause inhibition with an IC50 value of 40 µM and an associated Hill coefficient of 2.7. Similarly, ciclazindol (1 µM) had no significant effect on KATP channel activity following leptin addition in excised inside-out patches. 7. In conclusion, K(ATP) currents activated by diazoxide and leptin show different sensitivity to englitazone and ciclazindol. This may be due to differences in the mechanism of activation of KATP channels by diazoxide and leptin.