- A new class of pseudopeptide antagonists of the kinin B1 receptor containing alkyl spacers
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Four previously reported kinin receptor peptide antagonists, including the B1 receptor-selective peptides desArg10-HOE 140 (H-D-Arg-Arg-Pro-Hyp- Gly-Thi-Ser-D-Tic-Oic-OH) and B-9858 (H-Lys-Lys-Arg-Pro-Hyp-Gly-Igl-Ser-D- Igl-Oic-OH), have been modified by replacement of the central tetrapeptide Pro-Hyp-Gly-Xaa with linear alkyl spacers of variable length. The analogue of desArg10-HOE 140 containing the 11-aminoundecanoic acid as spacer, MEN 11575 [H-D-Arg-Arg-NH-(CH2)10-CO-Ser-D-Tic-Oic-OH], was found to be slightly more potent than the unmodified peptide (pA2 = 7.1) as a kinin B1 receptor antagonist in the rat ileum longitudinal smooth muscle assay. Moreover, MEN 11575 is devoid of residual agonist activity at the kinin B1 receptor (rat ileum) and antagonist activity at the kinin B2 receptor (guinea pig ileum longitudinal smooth muscle). Both these activities are displayed by the parent peptide desArg10-HOE 140. Therefore, despite its greatly simplified chemical structure, MEN 11575 shows an improved pharmacological profile in terms of both potency and selectivity, and it represents a good template for the development of new peptidomimetic kinin B1 receptor antagonists. We also report an attempt to investigate the conformational role of the flexible, linear spacer of MEN 11575 and to design more constrained analogues, possibly locked in the bioactive conformation, using semirigid spacers based on C(α)-tetrasubstituted α-amino acids of the family of 1-aminocycloalkane-1-carboxylic acids (Ac(n)c).
- Galoppini, Claudia,Meini, Stefania,Tancredi, Mariella,Di Fenza, Armida,Triolo, Antonio,Quartara, Laura,Maggi, Carlo A.,Formaggio, Fernando,Toniolo, Claudio,Mazzucco, Silvia,Papini, Annamaria,Rovero, Paolo
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- Versatile method for the detection of covalently bound substrates on solid supports by DART mass spectrometry
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Analysis of substrates directly on solid phase resins without the need for separate cleavage conditions remains an outstanding challenge in the field of solid phase synthesis. We now present the first example of simultaneous cleavage and mass spectrometri
- Sanchez, Laura M.,Curtis, Matthew E.,Bracamonte, Bianca E.,Kurita, Kenji L.,Navarro, Gabriel,Sparkman, O. David,Linington, Roger G.
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- Synthesis and structure-activity relationship studies of new endothelin pseudopeptide analogues containing alkyl spacers
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We replaced the Asp18-Ile19 dipeptide of the C-terminal ET analogue Ph-Ph-CH2-O-N=CH-CO-Phe-Asp-Ile-Ile-Trp-OH by alkyl spacers of various lengths to investigate the role of the aminoacidic central portion of the molecule and to define the N-terminal and C-terminal pharmacophoric regions of this analogue. The side-chains of the central dipeptide have been shown to be irrelevant for the binding of the molecule to the receptor, but the distance between the two postulated sites of interaction of the ligand with the ET(B) receptor appears to be fundamental.
- Galoppini, Claudia,Giusti, Laura,Macchia, Marco,Hamdan, Mahmoud,Mazzoni, Maria Rosaria,Calvani, Federico,Rovero, Paolo
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- Novel platelet-aggregation inhibitors
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Novel peptide mimetic compounds are provided which have useful activity as inhibitors of platelet aggregation. These compounds have the chemical structure STR1 wherein x=6 to 10, y=0 to 4, Z=H, COOH, CONH2 or C1-6 alkyl, Ar=phenyl, biphenyl or napthyl, each substituted with 1 to 3 methoxy groups, or an unsubstituted phenyl, biphenyl, napthyl, pyridyl or thienyl group, and Asp=aspartic acid residue.
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