Hydroxyl-substituted sulfonylureas as potent inhibitors of specific [3H]glyburide binding to rat brain synaptosomes.

We are seeking to discover potent CNS-active sulfonylureas with structural features that allow for the formation of several types of prodrugs. We report herein the syntheses of compounds comprising an initial series of hydroxyl-substituted analogues of the potent ATP-sensitive potassium channel blockers glyburide (glibenclamide) and gliquidone. Somewhat unexpectedly, several of the compounds were found to be comparably potent to glyburide as inhibitors of specific [(3)H]glyburide binding in rat brain preparations.

The Effect of Centrally Administered Glibenclamide, Tolbutamide and Diazoxide on Feeding in Rats.

While there are many theories on the control of feeding behavior that emphasize a role for energy substrates and their metabolism, the mechanism that couples changes in energy substrate supply and metabolism to alterations in food intake remains unclear. The purpose of the present project was to investigate the possibility that central ATP-sensitive potassium (KATP(+)) channels may serve as integrators between cellular energetics and alterations in neuronal activity that control feeding, such that pharmacologic manipulation of the channels would result in alterations in feeding behavior. Intracerebroventricular (ICV) injections of the KATP(+) channel blocker glibenclamide significantly increased feeding in fasted and fed male Sprague-Dawley rats.

Quinpirole-induced alterations of tail temperature appear as hyperalgesia in the radiant heat tail-flick test.

Several reports in the recent literature argue both for and against the importance of alterations of tail-temperature in the outcome of the tail-flick test. The data we present here support the assertion that drug-induced changes of tail-temperature may have a highly significant effect on tail-flick latency independent of drug-induced changes in nociception. We previously reported that peripherally administered injections of the dopamine agonist, quinpirole, produce significant reductions in the latency of response in the tail-flick test.