POTENTIATION OF EFFECTS OF EPINEPHRINE BY FLAVONOID ("VITAMIN P"-LIKE) COMPOUNDS. RELATION OF STRUCTURE TO ACTIVITY

¹ Scripps Metabolic Clinic, La Jolla, Calif. and the Department of Chemistry, University of California at Los Angeles

1. An isolated smooth muscle preparation is described for testing substances potentiating the action of epinephrine under these circumstances.

2. Some 70 compounds were examined for the relation between molecular structure and activity of flavonoid-like ("vit. P"-like) substances on this epinephrine effect.

3. The minimum molecular structure essential for high activity was predicted, synthesized and confirmed to have such high activity. It is 3 ,3',4'-trihydroxyflavone and has an activity about 16 times that of rutin, on a weight basis.

4. The epinephrine-potentiating effect of the compounds is due chiefly to metal chelation, although this is not the only possible mechanism.

5. The presence of an unsubstituted ortho-dihydroxybenzene nucleus, while present in many of the more active compounds, also is not a structural necessity.

6. A spectrophotometric method is described for measurement of the coppercatalyzed oxidation of epinephrine to one of its red oxidation products, such as adrenochrome. 36 compounds were tested by this method.

7. The activity series obtained by the isolated smooth muscle assay method does not coincide with that by the spectrophotometric method.

8. The activity series obtained by the isolated smooth muscle assay method does not correspond with capillary-fragility decreasing ("vit. P") activity as reported in the literature.

9. "Vitamin P"-like substances have no effect on the magnitude or duration of response of intestine to stimulation of the inhibitory mesenteric nerve, upon blood sugar levels in the presence or absence of epinephrine hyperglycemia, nor upon the preventative effect of epinephrine upon eggwhite edema in rats.

10. It is concluded that items 7 and 8 do not support the theory that "vit. P"-like substances act in the intact organism by inhibiting the metal-catalyzed oxidative destruction of epinephrine or sympathin and that the isolated intestinal segment response is not a valid assay method for "vitamin P" activity.

11. The metal chelating and anti-oxidant properties of the compounds studied may have other useful applications.