University of Hertfordshire

  • C. R. Albrightson
  • P. J. Bugelski
  • Theo Berkhout
  • B. Jackson
  • William D. Kerns
  • A.J. Organ
  • A. M. Badger
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Original languageEnglish
Pages (from-to)689-698
Number of pages10
JournalJournal of Pharmacology and Experimental Therapeutics
Volume272
Issue2
Publication statusPublished - 22 Feb 1995

Abstract

Azaspiranes 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.

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