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

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-(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.