ATP-sensitive potassium (Katp) channels have been identified in many excitable cell types, into which they play a wide variety of physiological roles. Such ionic channels have been depicted in pancreatic B-cells and have been shown to be tightly involved in the insulin secretory process. In vascular smooth muscle cells, Katp channels participate in the control of muscle tone. The potential and recognized therapeutic indications for potassium channel openers (PCOs) include the treatment of arterial hypertension, angina pectoris, androgenic alopecia... PCOs have also been proposed for the prevention and/or management of type I, type II diabetes, obesity, nesidioblastosis and insulinomas. In order to be used as therapeutic agents and to avoid side effects, PCOs need to express a potent activity associated with high tissue selectivity. By exploring a series of 4,6-disubstituted R/S-3,4-dihydro-2,2-dimethyl-2H-1-benzopyrans structurally related to (±)-cromakalim, we have recently identified compounds relatively potent and selective for the pancreatic Katp channel. Such compounds were bearing a bulky tert-butyloxycarbonylamino group at the 6-position as well as, at the 4-position, a phenylthiourea moiety substituted on the phenyl ring by a meta or a para-electron- withdrawing group such as Cl or CN. In the light of such data, the present work aimed at exploring the influence of other groups at the 6-position, keeping the same substitutions at the 4-position. Preliminary results indicated that the new molecules inhibited the insulin secretory rate and affected the vascular smooth muscle contractile activity. Radioisotopic experiments further revealed that the mechanism of action was related to the activation of Katp channels.