Recent studies have demonstrated that selective activation of pancreatic ATP-sensitive potassium (KATP) channels could be of clinical value in the treatment of type I and type II diabetes, obesity, and hypersinsulinemia. Taking into account these promising therapeutic opportunities, we have explored the 3-alkylamino-4H-1,2,4-pyrido- and 3-alkylamino-4H-1,2,4-benzothiadiazine 1,1-dioxide families. Among these series, numerous drugs were identified as highly potent and selective openers of either the pancreatic or the aortic KATP channels. Thanks to comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA), quantitative structure-activity relationship approaches using more than 100 compounds, pharmacophoric models explaining the activity and selectivity of the drugs have been elaborated. These models highlighted the importance of several chemical regions for KATP channel activation and could be very helpful for future improvement of drug potency, selectivity, or both. Moreover, an original CoMSIA analysis, using a selectivity index (SI) as a dependent variable, was also performed with the aim of identifying the structural parameters influencing tissue selectivity.