Three-dimensional database searching based on the pharmacophore model of the known maxi-K opener NS-004 (1) and electrophysiological evaluation led to the discovery of flavonoids (3c and 3d) as openers of the cloned maxi-K channel mSlo expressed in Xeraopus luevis oocytes. The cyclic constrained flavonoids were found to be more efficacious than the acyclic phloretin. 0 1997 Bristol-Myers Squibb. Published by Elsevter Sctence Ltd. Ca2+-Dependent, large conductance potassium channels (also called maxi-K or BK channels) are distributed in many cell types including neurons and muscle cells, and are thought to play important roles in cellular excitation and function. 4S These channels. acted upon by a specific modulator, are potential therapeutic targets for a number of disease states. 6,7 The recent discovery that the benzimidazolone derivative NSO04 (1)8-' 1 is a maxi-K opener has prompted a search for more efficacious and selective openers for maxi-K channels. Since then, several groups have reported new classes of maxi-K openers, t2-'6 which have been reviewed.697 We report here the successful identification of novel maxi-K openers using a 3-D pharmacophore model and the results of subsequent electrophysiological evaluation. l,NS-004 2 Pbarmacophore Model and Database Search
On the basis of NS-004 and the structure-activity relationships revealed previously by Meanwell and coworkers,12 the phenolic OH and carbonyl oxygen were thought to be a surrogate of carboxyhc acid. The fact that 1 and 2 are equally effective indicates some flexibility of these bioisosterest2 Alternatively, the weakly acidic amide hydrogen and the amide carbonyl oxygen were postulated to surrogate a carboxylic acid and were critical for the maxi-K activity. This seems to be reasonable since imidazolone has been suggested to mimic a phosphate. t7-t9 Furthermore, electron-withdrawing groups attached to the heterocyclic nucleus in 1 and 2,