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.
journal_name
Eur J Pharmacoljournal_title
European journal of pharmacologyauthors
Chan SL,Pallett AL,Clews J,Ramsden CA,Chapman JC,Kane C,Dunne MJ,Morgan NGdoi
10.1016/s0014-2999(98)00466-xsubject
Has Abstractpub_date
1998-08-14 00:00:00pages
67-76issue
1eissn
0014-2999issn
1879-0712pii
S0014-2999(98)00466-Xjournal_volume
355pub_type
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