STRUCTURE-ACTIVITY RELATIONSHIP OF COVALENTLY DIMERIZED INSULIN DERIVATIVES - CORRELATION OF PARTIAL AGONIST EFFICACY WITH CROSS-LINKAGE ATLYSINE B29

The effects of 7 covalently dimerized insulin derivatives on glucose t ransport in differentiated 3T3-L1 cells were investigated. Symmetric c ross-linkage at lysine B29 with a bridge of 2 (oxalyl), 8 (suberoyl) o r 12 (dodecanedioyl) carbon atoms produced derivatives with essentiall y unaltered receptor binding affinity but largely reduced intrinsic ac tivity. Regardless of the chain length, these derivatives inhibited th e effect of submaximal insulin concentrations. Insulin derivatives cro ss-inked at phenylalanine B1 or asymmetrically at B1/B29 were full ago nists of the insulin receptor. When lysine B29 was cross-linked with t he inactive desoctapeptide(B23-B30)insulin at phenylalanine B1, the in trinsic activity of the resulting dimer was lower than that of insulin , but higher than that of the symmetric B29-dimers. It is concluded th at linkage at the B29-lysines, and not at the B1-phenylalanine, leads to partial agonism of dimerized insulin derivatives, regardless of the length of the crosslinker.