Alcohol absorption inhibitors from bay leaf (Laurus nobilis): Structure-requirements of sesquiterpenes for the activity

Through a bioassay-guided separation using inhibitory activity on blood eth anol elevation in oral ethanol-loaded rat, various sesquiterpenes having an alpha-methylme-gamma-butyrolactone moiety, costunolide (1), dehydrucostus lactone (2), zaluzanin D (3), reynosin (4), santamarine (5), 3 alpha-acetox yeudesma-1,4(15),11(13)-trien-12,6 alpha-olide (6) and 3-oxoeudesma-1,4,11( 13)-trien-12,6 alpha-olide (7), were isolated as the active principle from the leaves of Laurus nobilis (bay leaf, laurel). In order to characterize t he structure requirement for the activity, several reduction products (2a-2 d) and amino acid adducts (2e, 2f) of the alpha-methylene-gamma-butyrolacto ne moiety were synthesized from 2 and the inhibitory activities of these se squiterpenes, together with alpha-methylene-gamma-butyrolactone (12) and it s related compounds (13-16), were examined. These results indicated that th e gamma-butyrolactone or gamma-butyrolactol moiety having ol-methylene or g amma-methyl group was essential for the inhibitory activity on ethanol abso rption. Since 1, 2 and 12 showed no significant effect on glucose absorptio n, these sesquiterpenes appeared to selectively inhibit ethanol absorption. In addition, the acute toxicities of 1 and 2 in a single oral administrati on were found to be lower than that of 12. (C) 2000 Elsevier Science Ltd. A ll rights reserved.