Structure-activity relationships of aminoalkyl and -aryl glycosides having insulin-like activity

A number of alkyl, aryl, and aralkyl glycosides (mono- and disaccharides) substituted in the aglycon with a primary amino group have been found to exert insulin-like activity on rat adipocytes in vitro. Systematic variations in the saccharide configuration, glycosidic linkage, aglycon moiety, and sugar substitution pattern were investigated to delineate structure-activity relationships. A high degree of structural specificity was observed. Maximal insulin mimicking activity was obtained with the 6-aminohexyl 1-thio-D-mannopyranosides; the beta anomer was more active than the alpha anomer. Modification of the sugar hydroxyl groups resulted, in most cases, in partial or complete loss of biological activity at the levels tested; however, in a few instances, sugar-modified derivatives did show enhanced insulin-like effects. Specific structural types evaluated are discussed in greater detail. 6-Aminohexyl 1-thio-beta-D-mannopyramoside also exhibited in vivo insulin-like effects on both diaphragm muscle and omental adipose tissues. The specificities for the sugar as well as the aglycon portions of these carbohydrate derivatives suggest that both parts of the molecule are involved in the expression of the full biological activity observed; their respective roles in the mechanism of the insulin-like activity are discussed.