Highly potent and stereoselective effects of the benzoic acid derivative AZ-DF 265 on pancreatic beta-cells.
1. Mouse islets were used to define the characteristics and study the mechanisms of the stimulation of insulin release by compound AZ-DF 265, 4-[[N-(alpha-phenyl-2-piperidino-benzyl) carbamoyl]methyl] benzoic acid, a substituted benzoic acid with an asymmetric carbon atom. 2. At a non-stimulatory concentration of glucose (3 mM), (-)-AZ-DF 265 reversibly inhibited 86Rb efflux from islet cells, depolarized the beta-cell membrane, induced electrical activity, stimulated 45Ca efflux, and triggered insulin release. Maximum inhibition of 86Rb efflux occurred at 0.03 microM (-)-AZ-DF 265, whereas the threshold concentration for stimulation of release was 0.1 microM. Omission of extracellular Ca2+ abolished all effects of the drug but the inhibition of 86Rb efflux. 3. At a stimulatory concentration of glucose (10 mM), (-)-AZ-DF 265 reversibly increased 86Rb efflux, potentiated electrical activity, augmented 45Ca efflux, and increased insulin release. Maximum stimulation of 86Rb efflux and insulin release was obtained with 0.03 microM (-)-AZ-DF 265. Omission of extracellular Ca2+ abolished all effects of the drug. 4. The potency of (-)-AZ-DF 265 was similar to that of glibenclamide, whereas the (+)-enantiomer was about 10 times less potent on 86Rb efflux and insulin release. 5. It is concluded that, like sulphonylureas, compound AZ-DF 265 decreases K+ permeability of the beta-cell membrane and thereby causes depolarization. This activates voltage-dependent Ca channels, permits Ca2+ influx and eventually stimulates insulin release. Its stereoselectivity may help to elucidate the mechanisms of K channel blockade and, hence, lead to the design of more potent and specific insulinotropic drugs.
Garrino
M G
MG
Unité de Diabétologie et Nutrition, University of Louvain, Brussels, Belgium.
Henquin
J C
JC
D000818:Animals; D002132:Calcium Radioisotopes; D005260:Female; D005947:Glucose / Q000494:pharmacology; D066298:In Vitro Techniques; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D010880:Piperidines / Q000494:pharmacology*; D011188:Potassium / Q000378:metabolism; D012414:Rubidium Radioisotopes; D013237:Stereoisomerism
D002132:Calcium Radioisotopes; D010880:Piperidines; D012414:Rubidium Radioisotopes; C055301:AZ-DF 265; D005947:Glucose; D011188:Potassium