title: Characterisation of new efaroxan derivatives for use in purification of imidazoline-binding sites.
abstract: The insulin secretagogue activity of certain imidazoline compounds is mediated by a binding site associated with ATP-sensitive K+ (K(ATP)) channels in the pancreatic beta-cell. We describe the effects of a series 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 functional interaction of the ligand with the islet imidazoline binding site. Modification of the imidazoline ring to an imidazole to generate 2-(2-ethyl-2,3-dihydrobenzo[b]furan-2-yl)-1H-imidazole (KU14R) resulted in loss 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(ATP) channels by efaroxan in patch clamp experiments. Application of KU14R alone resulted in a modest reduction in K(ATP) channel opening, suggesting that it may display weak partial agonism, at least in patch-clamp experiments.
authors.affiliation: Department of Biological Sciences, University of Keele, Staffs, UK.
authors.forename: S L
authors.initials: SL
authors.lastname: Chan
authors.forename: A L
authors.initials: AL
authors.lastname: Pallett
authors.forename: J
authors.initials: J
authors.lastname: Clews
authors.forename: C A
authors.initials: CA
authors.lastname: Ramsden
authors.forename: J C
authors.initials: JC
authors.lastname: Chapman
authors.forename: C
authors.initials: C
authors.lastname: Kane
authors.forename: M J
authors.initials: MJ
authors.lastname: Dunne
authors.forename: N G
authors.initials: NG
authors.lastname: Morgan
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000737:chemistry*; D000818:Animals; D001572:Benzofurans / Q000737:chemistry* / Q000494:pharmacology*; D002478:Cells, Cultured; D005260:Female; D007093:Imidazoles / Q000737:chemistry* / Q000494:pharmacology*; D054755:Imidazoline Receptors; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers; D051381:Rats; D017208:Rats, Wistar; D011955:Receptors, Drug / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000302:isolation & purification*; D013329:Structure-Activity Relationship
chemical_list: D000317:Adrenergic alpha-Antagonists; D001572:Benzofurans; D007093:Imidazoles; D054755:Imidazoline Receptors; C106086:KU 14R; D026902:Potassium Channel Blockers; D011955:Receptors, Drug; D000255:Adenosine Triphosphate; C062597:efaroxan