THE CHOLESTEROL DERIVATIVE OF A TRIANTENNARY GALACTOSIDE WITH HIGH-AFFINITY FOR THE HEPATIC ASIALOGLYCOPROTEIN RECEPTOR - A POTENT CHOLESTEROL-LOWERING AGENT

Cholesterol-derivatized galactosides have been devised in order to ind uce liver uptake of lipoproteins via the galactose-recognizing asialog lycoprotein receptor in the liver. In this study we describe the deriv atization of a newly developed triantennary cluster galactoside having high affinity for the asialoglycoprotein receptor, yl]methyl]-N-alpha -[1-(6-methyladipyl)]glycinamide (TG(20 Angstrom)) with cholesterol. H ereto, TG(20 Angstrom) was coupled to glycine-(5-cholesten-3 beta-yl e ster) in the presence of enzotriazol-1-yloxy)tris(dimethylamino)phosph onium hexafluorophosphate, affording, l)methoxymethyl]methyl]N-alpha-[ 1-(6-5-cholesten-3 beta-yloxy)glycyl)adipyl]glycinamide (TG(20 Angstro m)C) in 46% yield. This compound is an amphiphilic, water-soluble comp ound. In aqueous solution it readily formed small micelles (4.9 +/- 1. 2 nm) consisting of approximately 20 molecules. Upon incubation with h uman serum, TG(20 Angstrom)C spontaneously incorporated into the most prominent serum lipoproteins, i.e., low-density lipoprotein (LDL) and high-density lipoprotein (HDL), thereby inducing an increase in buoyan t density of these lipoproteins. The integrity of HDL and LDL, as judg ed from particle size analysis of both lipoproteins, was not altered b y incubation with up to 0.33% of TG(20 Angstrom)C (w/v). Following int ravenous bolus injection into rats, TG(20 Angstrom)C induced a dose-de ],endent decrease in the serum cholesterol content of maximally 44%, a t a dose of 1.9 mg kg(-1). This makes TG(20 Angstrom)C at least 30-fol d more effective than the previously developed pyranosyl)methyl]methyl ]-N-alpha-[4-(5-cholesten-3 beta-yloxy)succinyl]glycinamide (TG(4 Angs trom)C, provided with a cluster galactoside that displayed a 2000-fold lower affinity for the asialoglycoprotein receptor than TG(20 Angstro m). In conclusion, the hypocholesterolemic activity of a cholesterylat ed galactoside can be strongly enhanced by using a cluster galactoside with higher affinity for the asialoglycoprotein receptor.