DEVELOPMENT OF CHLORIDE CHANNEL MODULATORS

Chloride channels are ubiquitously distributed, biophysically varied a nd functionally diverse. Despite the known contribution of chloride ch annels to the physiology of various cell types and the pathology of se veral diseases, high affinity ligands are not available to study these channels. Here we report the iterative and integrated use of ion chan nel kinetic analysis and computational chemical methods in the develop ment of high affinity blockers of the outwardly rectifying chloride ch annel (ORCC). Kinetic analysis, with emphasis on estimation of the blo ck time constant as determined from critical closed time plots, was us ed to guide the synthesis of new disulfonic stilbene derivatives. Comp utational chemical methods were used to deduce the important features of the disulfonic stilbene molecule necessary for potent blockade of O RCC and ultimately led to the discovery of the calixarenes. Para-sulfo nated calixarenes were found to be potent blockers of ORCC with subnan omolar inhibition constants and exceptionally long block times.