Continuing studies on modifications of potent cyclic pentapeptide endothelin (ET) receptor antagonists, represented by BQ-123, and potent linear tripeptide derivative ET receptor antagonists, represented by BQ-788, are described herein. The introduction of D-tryptophan analogues with C-2 substituents in these peptidic ET antagonists resulted in potent ET receptor antagonists with various ETA/ETB subtype selectivity. Combined ETA/ETB receptor antagonists were found in both cyclic pentapeptide and linear tripeptide series with 2-halo- and 2-methyl-D-tryptophans. In contrast, compounds with 2-cyano-D-tryptophan were ETB receptor-selective antagonists. The C-2 substituent of the D-tryptophanyl residue appeared to be very important for the discrimination of ETA/ETB subtype selectivity of the antagonists. The potent ET receptor antagonists with various ETA/ETB subtype selectivity synthesized in this study may be useful tools for elucidating the physiological and pathophysiological roles of ET and ET receptors.

The lipopolysaccharide (LPS) of enterobacteria frequently contains various numbers of charged non-stoichiometric substituents such as phosphate (P) and ethanolamine (EtN) groups and a third residue of 3-deoxy-D-manno-2-octulosonic acid (KDO) on the R-core polysaccharide backbone. These substituents can modify the biological activities of LPS including varying the stability of the outer membrane, tolerance to cationic antibiotics, pathogenicity, and sensitivity to enterobacteria bacteriophages. These diverse substituents can be clearly detected in degraded samples of LPS from E. coli C using electrospray ionization single quadrupole mass spectrometry (ESI-Q-MS) from a 0.1 mg/mL solution in a 50:50 mixture of methanol and 10 mM ammonium acetate (pH 6.8). The O-deacylated derivative showed multiple peaks of [M-3H](3-) ions which corresponded to species having up to eight phosphates, two ethanolamines, and an additional KDO on the backbone of Hex(5) Hep(3) KDO(2) GlcN(2) C14:0(3-OH)(2). The major components of the O,N-deacylated derivative were the species associated with four and five phosphates on Hex(5) Hep(3) KDO(2) GlcN(2). The polysaccharide portion of LPS also revealed species which corresponded to Hex(5) Hep(3) KDO associated with two to four phosphates and an ethanolamine. The present method was proved to be useful to investigate the structural diversity of enterobacterial LPS.

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