Porcine glucagon has been reacted with a series of alkyl imidates. The ɛ‐amino group and both the α and ɛ‐amino groups were modified and the subsequent glucagon derivatives were purified by ion‐exchange chromatography and characterized. The modified glucagons were compared with native glucagon in their ability to activate hepatic adenylate cyclase and to compete with 125I‐glucagon for binding to sites specific for glucagon in hepatic plasma membranes. Nɛ‐acetamidino glucagon was as biologically potent, in both activity and binding, as native glucagon, whereas Nɛ‐4 hydroxyphenylamidinoglucagon required a twofold higher concentration to obtain similar levels. These findings suggest that modification through the ɛ‐amino group with alkyl imidates possessing reporter groups should result in glucagon derivatives with significant biological potency, thus providing a new approach to the study of this peptide hormone. Amidination of both ɛ and α‐amino groups resulted in glucagon derivatives which were partial agonists with respect to adenylate cyclase activation and which displayed unexpected anomylous behavior on chromatography.
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