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Mammalian macrophages contain a transport system that binds and internalizes glycoproteins with exposed mannose residues. This system and analogous systems on other types of cells require substrates to bear multiple nonreducing terminal residues ofthe appropriate sugar for effective uptake. Small multivalent synthetic glycopeptides with mannose residues covalently linked through a spacer arm to the a-and e-amino groups of lysine, dilysine, and trilysine are competitive inhibitors of rat alveolar macrophage uptake of the neoglycoprotein mannosyl-bovine serum albumin with inhibition constants in the ,uM range. Various compounds could be covalently attached to the a-carboxyl group of these glycopeptides with substantial retention of#hibi-tory potency. This uptake system does not recognize galactose residues, and the galactosyl analog of an inhibitory mannosylpeptide did not inhibit uptake of mannosyl-bovine serum albumin. The trimannosyldilysine ligand is not only an inhibitor but also a substrate for specific uptake by macrophages, as shown with an 125F labeled derivative. Macrophages bound 6.4 x 105 molecules per cell at 0°C with a dissociation constant of 2 ,uM. At 21°C the cells could internalize the labeled conjugate with an apparent Michaelis constant of 6 ,uM and a maximal velocity of 1.7 x 105 molecules per min per cell. The dissociation constant and Michaelis constant are similar to the inhibition constant of 9 ,uM determined at 21°C for inhibition by this conjugate of mannosyl-bovine serum albumin uptake. These synthetic substrates may be useful in targeting pharmacologic agents to macrophages, and analogous compounds may target such agents to other types of cell. Macrophages play important roles in immune responses, in chronic inflammation, and in some parasitic diseases. In each case, it may be useful to deliver pharmacologic agents selectively to macrophages, particularly subpopulations of macrophages such as those in inflamed joints or in lymph nodes. We are attempting to determine whether the carbohydrate-specific glycoprotein uptake system of macrophages (1) can be used for macrophage-specific drug targeting.Mammalian macrophages specifically bind and internalize glycoproteins bearing exposed residues of mannose, N-acetylglucosamine, glucose, and L-fucose (1-3). The substrate glycoproteins are degraded within lysosomes, while the receptor component of the uptake system apparently functions repeatedly without being degraded (4). A protein that seems to be the receptor for this system has been isolated from rabbit liver (5) and serum (6) and from rat liver (7) and lymph nodes (8). The components and operation of the macrophage glycoprotein uptake system are quite similar to those of the galactose-specific mammalian hepatocyte system described by Ashwell, Morell, and coworkers (9-11). Analogous systems with other sugar specificities have also been found (12)(13)(14)(15) In the hope that these glycoprotein uptake systems may be useful in tissue-specific delivery of pharmacologic agents, we have...

Various numbers of D-mannose residues have been attached via spacer arms to lysine, dilysine, and oligolysine backbones. These D-mannosyl peptide analogues were found to be potent competitive inhibitors of the uptake of 125I-labeled D-mannose-bovine serum albumin conjugate by rat alveolar macrophages. The inhibitory potency of these synthetic ligands increased with increasing number of carbohydrate moieties. The chirality of the peptide backbone did not appear to play a major role in binding, whereas variations of the length and linkage of the spacer arm notably affected the inhibitory activities. The saccharide specificity of the macrophage receptor was demonstrated by the inactivity of the corresponding D-galactosyl peptide analogues. The L-fucosyl peptide derivative was only weakly active. The trimannosyldilysine ligand (KI = 3.9 microM) and its analogues are potentially useful in selective delivery of therapeutic agents to macrophages.

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The six (racemic or meso) isomers of 3,4-dimethyl-2,5-bis(3,4-dimethoxyphenyl)tetrahydrofuran and four corresponding desmethyl analogues were prepared and assayed as inhibitors of platelet activating factor (PAF) receptor binding to rabbit platelet plasma membranes. The inhibition by these isomers is stereodependent and varies with the gross shape of the molecules as determined by the molecular mechanics program MM2. The most potent PAF antagonist in this group of compounds is trans-2,5-bis(3,4,5-trimethoxyphenyl)tetrahydrofuran (L-652,731, 14) with an IC50 of 0.02 microM.

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Some 2-(substituted phenyl)oxazolo[4,5-b]pyridines and 2-(substituted phenyl)oxazolo[5,4-b]pyridines have good antiinflammatory and analgesic activity. A few possess activity comparable to phenylbutazone or indomethacin without producing the irritation in the gastrointestinal tract that acidic antiinflammatory compounds cause.