The imidazoline SL 84.0418 shows stereoselectivity in blocking alpha 2-adrenoceptors but not ATP-sensitive K+ channels in pancreatic B-cells.
The novel alpha 2-adrenoceptor antagonist SL 84.0418 (2-(4,5-dihydro-1H-imidazol-2-yl)-1,2,4,5-tetrahydro-2-propyl-pyrrolo[3, 2,1- hi]-indole hydrochloride) is a racemic mixture of a (-) enantiomer (SL 86.0714) and a (+) enantiomer (SL 86.0715 or deriglidole). It was recently reported to inhibit alpha 2-adrenoceptors and ATP-sensitive K+ channels in mouse pancreatic B-cells, and to increase insulin release. We have now studied the stereospecificity of these responses with isolated mouse islets. Both enantiomers were equipotent in potentiating insulin release induced by 15 mM glucose alone. SL 86.0714 and deriglidole were also equally effective in inhibiting 86Rb efflux from islets perifused with a low-glucose medium, and in reversing the inhibition of glucose-induced insulin release caused by the opening of ATP-sensitive K+ channels with diazoxide. In contrast, deriglidole was approximately 100-fold more potent than SL 86.0714 in reversing the inhibition of insulin release caused by the activation of alpha 2-adrenoceptors with clonidine. The effects of SL 84.0418 are thus stereoselective on alpha 2-adrenoceptors, but not on ATP-sensitive K+ channels of pancreatic B-cells.
Jonas
J C
JC
Unit of Endocrinology and Metabolism, University of Louvain, Brussels, Belgium.
Garcia-Barrado
M J
MJ
Angel
I
I
Henquin
J C
JC
D000255:Adenosine Triphosphate / Q000378:metabolism; D058669:Adrenergic alpha-2 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000818:Animals; D003000:Clonidine / Q000494:pharmacology; D003981:Diazoxide / Q000494:pharmacology; D005260:Female; D005947:Glucose / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D011188:Potassium / Q000378:metabolism; D015221:Potassium Channels / Q000187:drug effects* / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology*; D013237:Stereoisomerism
D058669:Adrenergic alpha-2 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists; D007211:Indoles; D007328:Insulin; D015221:Potassium Channels; D011758:Pyrroles; C074936:SL 84.0418; D000255:Adenosine Triphosphate; D005947:Glucose; D003000:Clonidine; D003981:Diazoxide; D011188:Potassium