Inhibition of alloxan-induced hyperglycaemia by compounds of similar molecular structure.
In this study we have shown that a range of compounds that are structurally similar to alloxan are able to protect mice against the diabetogenic effect of alloxan. The compounds include a group of five barbiturates, a group of five hydantoins, the methylxanthines caffeine and theophylline, the related compound uric acid, and ethosuximide. They were injected intraperitoneally prior to intravenous injection of alloxan, and blood glucose concentration was used as an index of alloxan toxicity. The salient structural feature possessed by all of these protective compounds is a pair of carbonyl oxygen atoms separated by a distance of 4.5 A and projecting from an approximately planar heterocyclic five- or six-membered ring; in all cases the carbonyl groups are separated by a ring nitrogen. We suggest that this feature is required for the protective effect of these compounds. In order to test further the requirement for two ring carbonyl groups, we also examined the effects of two compounds containing hydroxyl groups projecting from a six-membered ring, inositol and glucuronic acid. In agreement with previous studies on hexoses, we found that the effects of compounds such as these are unpredictable, with inositol protecting against alloxan toxicity but glucuronic acid not. We are unable to identify the critical difference in structure between these two compounds.
Edwardson
J M
JM
Department of Pharmacology, University of Cambridge, U.K.
Dean
P M
PM
D000481:Allantoin / Q000627:therapeutic use; D000496:Alloxan / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D000818:Animals; D001463:Barbiturates / Q000627:therapeutic use; D001786:Blood Glucose / Q000187:drug effects; D002110:Caffeine / Q000627:therapeutic use; D005013:Ethosuximide / Q000627:therapeutic use; D006943:Hyperglycemia / Q000139:chemically induced / Q000517:prevention & control*; D007294:Inositol / Q000627:therapeutic use; D008297:Male; D051379:Mice; D010672:Phenytoin / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D013806:Theophylline / Q000627:therapeutic use; D014527:Uric Acid / Q000627:therapeutic use
D001463:Barbiturates; D001786:Blood Glucose; D014527:Uric Acid; D000481:Allantoin; D002110:Caffeine; D007294:Inositol; D005013:Ethosuximide; D010672:Phenytoin; D000496:Alloxan; D013806:Theophylline