Highly potent and stereoselective effects of the benzoic acid derivative AZ-DF 265 on pancreatic β-cells

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Abstract
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-(α-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 β-cell membrane, induced electrical activity, stimulated 45Ca efflux, and triggered insulin release. Maximum inhibition of 86Rb efflux occurred at 0.03 μm (-)-AZ-DF 265, whereas the threshold concentration for stimulation of release was 0.1 μm. 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 μm (-)-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 β-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.