CHARACTERIZATION OF NEW EFAROXAN DERIVATIVES FOR USE IN PURIFICATION OF IMIDAZOLINE-BINDING SITES

The insulin secretagogue activity of certain imidazoline compounds is mediated by a binding site associated with ATP-sensitive K+ (K-ATP) ch annels in the pancreatic beta-cell. We describe the effects of a serie s of structural modifications to efaroxan on its activity at this site . Substitution of amino-, nitro- or azide- groups onto the 5-position of the benzene ring of efaroxan did not significantly affect the funct ional interaction of the ligand with the islet imidazoline binding sit e. Modification of the imidazoline ring to an imidazole to generate -e thyl-2,3-dihydrobenzo[b]furan-2-yl)-1H-imidazole (KU14R) resulted in l oss of secretagogue activity. Indeed, this reagent appeared to act as an imidazoline antagonist since it blocked the secretory responses to imidazoline compounds and also inhibited the blockade of beta-cell K-A TP channels by efaroxan in patch clamp experiments. Application of KU1 4R alone resulted in a modest reduction in K-ATP channel opening, sugg esting that it may display weak partial agonism, at least in patch-cla mp experiments. (C) 1998 Elsevier Science B.V. All rights reserved.