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dc.contributor.authorAlbrightson, C. R.
dc.contributor.authorBugelski, P. J.
dc.contributor.authorBerkhout, Theo
dc.contributor.authorJackson, B.
dc.contributor.authorKerns, William D.
dc.contributor.authorOrgan, A.J.
dc.contributor.authorBadger, A. M.
dc.identifier.citationAlbrightson , C R , Bugelski , P J , Berkhout , T , Jackson , B , Kerns , W D , Organ , A J & Badger , A M 1995 , ' Separation of immunomodulatory and cholesterol-lowering activities of heterocyclic azaspiranes ' , Journal of Pharmacology and Experimental Therapeutics , vol. 272 , no. 2 , pp. 689-698 .
dc.identifier.otherPURE: 7130610
dc.identifier.otherPURE UUID: cf7db76a-ecd8-469d-99ce-c768f8b2cebc
dc.identifier.otherScopus: 0028889906
dc.identifier.otherPubMed: 7853183
dc.description.abstractAzaspiranes are novel immunomodulators which are effective in a variety of autoimmune diseases. One azaspirane analog, SK and F 105685 (N,N-dimethyl- 8,8-dipropyl-2-azaspiro [4.5] decane-2-propanamine dihydrochloride), caused a decrease in total serum cholesterol in dogs after oral administration. To determine whether an effect on cholesterol was common to this class of compounds, the immunomodulatory activity was compared with the cholesterol- lowering activity of six azaspirane analogs. The compounds were given to beagles at a dose of 1 mg/kg p.o. for 28 days, and the effect on serum cholesterol was determined. The results from this study showed a clear dissociation between the immunomodulatory and hypocholesterolemic activities of these compounds. Studies performed to determine the mechanism of the decrease in serum cholesterol caused by SK and F 105685 indicated that it was not due to inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase or acyl-CoA:cholesterol acyltransferase activities, or to a potentiation of cholesterol-7α-hydroxylase activity. In addition, analysis by gas chromatography of the nonsaponifiable sterol fraction in dog plasma after treatment with SK and F 105685 or SK and F 106333 showed a decrease in cholesterol and an accumulation of lathosterol and an unknown sterol, indicating that the conversion of these sterols is inhibited and cholesterol synthesis is blocked at these steps. SK and F 105685 affected the sterol profile in human hepatoblastoma cells (Hep G2) in a similar way. Characterization of the unknown sterol by gas chromatography and mass spectrometry indicated that the unknown sterol is very similar to cholesterol and lathosterol, but its identity has yet to be established. These results show that the hypocholesterolemic effects of azaspiranes are related to inhibition of one or more of the final steps in the biosynthetic pathway of cholesterol.en
dc.relation.ispartofJournal of Pharmacology and Experimental Therapeutics
dc.titleSeparation of immunomodulatory and cholesterol-lowering activities of heterocyclic azaspiranesen
dc.contributor.institutionSchool of Life and Medical Sciences
dc.contributor.institutionDepartment of Pharmacy
dc.contributor.institutionHealth & Human Sciences Research Institute
dc.contributor.institutionMedicinal and Analytical Chemistry
dc.description.statusPeer reviewed
rioxxterms.typeJournal Article/Review

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