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5 results on '"Quartara L"'

1. Agonist Activity at the Kinin B1 Receptor:  Structural Requirements of the Central Tetrapeptide

Author

Rovero, P., Pellegrini, M., Fenza, A. Di, Meini, S., Quartara, L., Maggi, C. A., Formaggio, F., Toniolo, C., and Mierke, D. F.

Abstract

A series of analogues of desArg9-Lys-bradykinin (BK), Lys-Arg-X-Acnc-X-Ser-Pro-Phe, in which the spacer X-Acnc-X replaces the central tetrapeptide Pro-Pro-Gly-Phe of BK, have been synthesized and functionally characterized at the B1 receptor. The 1-aminocycloalkane-1-carboxylic acids (Ac6c, Ac7c, Ac8c, Ac9c, Ac12c) were incorporated to impart conformational constraint and probe the importance of the hydrophobicity of the residue in the central position. The linker is varied in length (X = Gly, βAla, γAbu) to examine the optimal distance between the biologically important residues at the N- and C-termini. The biological assays indicate that the optimal length is obtained with X = Gly, with reduced activities for the longer linkers. Although the size of the central cyclic amino acid does not significantly alter the biological activity, the hydrophobic residue Acnc which may tether the peptide in the membrane environment is required (Lys-Arg-Gly-Gly-Gly-Ser-Pro-Phe is inactive). Two of the analogues, Lys-Arg-Gly-Ac7c-Gly-Ser-Pro-Phe and Lys-Arg-γAbu-Ac7c-γAbu-Ser-Pro-Phe, have been structurally characterized in the presence of a zwitterionic lipid environment by high-resolution NMR. Both compounds have similar structural features, differing greatest in the distance between the termini (9 and 15 Å for the Gly- and γAbu-containing analogues, respectively). The correlation of the smaller distance with activity at the B1 receptor is in complete accord with the results from our previous examination of Lys-Arg-NH-(CH2)11-CO-Ser-Pro-Phe. With the results from this series of compounds we are beginning to define some of the molecular descriptors important for activity at the B1 BK receptor.

Published
2001

2. A New Class of Pseudopeptide Antagonists of the Kinin B<INF>1</INF> Receptor Containing Alkyl Spacers

Author

Galoppini, C., Meini, S., Tancredi, M., Fenza, A. Di, Triolo, A., Quartara, L., Maggi, C. A., Formaggio, F., Toniolo, C., Mazzucco, S., Papini, A., and Rovero, P.

Abstract

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 Cα-tetrasubstituted α-amino acids of the family of 1-aminocycloalkane-1-carboxylic acids (Acnc).

Published
1999

3. Design and synthesis of novel sulfonamide-containing bradykinin hB2 receptor antagonists. 2. Synthesis and structure-activity relationships of alpha,alpha-cycloalkylglycine sulfonamides.

Author

Fattori D, Rossi C, Fincham CI, Caciagli V, Catrambone F, D'Andrea P, Felicetti P, Gensini M, Marastoni E, Nannicini R, Paris M, Terracciano R, Bressan A, Giuliani S, Maggi CA, Meini S, Valenti C, and Quartara L

Subjects
Animals, Blood Pressure drug effects, Bronchoconstriction drug effects, Bronchodilator Agents chemistry, Bronchodilator Agents pharmacology, CHO Cells, Cricetinae, Cricetulus, Drug Design, Guinea Pigs, Humans, Ileum drug effects, Ileum physiology, In Vitro Techniques, Inositol Phosphates biosynthesis, Male, Muscle Contraction drug effects, Muscle, Smooth drug effects, Muscle, Smooth physiology, Ornithine chemical synthesis, Ornithine chemistry, Ornithine pharmacology, Stereoisomerism, Structure-Activity Relationship, Sulfonamides chemistry, Sulfonamides pharmacology, Bradykinin B2 Receptor Antagonists, Bronchodilator Agents chemical synthesis, Ornithine analogs & derivatives, Sulfonamides chemical synthesis
Abstract

Recently we reported on the design and synthesis of a novel class of selective nonpeptide bradykinin (BK) B2 receptor antagonists (J. Med. Chem. 2006, 3602-3613). This work led to the discovery of MEN 15442, an antagonist with subnanomolar affinity for the human B2 receptor (hB2R), which also displayed significant and prolonged activity in vivo (for up to 210 min) against BK-induced bronchoconstriction in the guinea-pig at a dose of 300 nmol/kg (it), while demonstrating only a slight effect on BK-induced hypotension. Here we describe the further optimization of this series of compounds aimed at maximizing the effect on bronchoconstriction and minimizing the effect on hypotension, with a view to developing topically delivered drugs for airway diseases. The work led to the discovery of MEN 16132, a compound which, after intratracheal or aerosol administration, inhibited, in a dose-dependent manner, BK-induced bronchoconstricton in the airways, while showing minimal systemic activity. This compound was selected as a preclinical candidate for the topical treatment of airway diseases involving kinin B2 receptor stimulation.

Published
2007
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4. Design and synthesis of novel sulfonamide-containing bradykinin hB2 receptor antagonists. 1. Synthesis and SAR of alpha,alpha-dimethylglycine sulfonamides.

Author

Fattori D, Rossi C, Fincham CI, Berettoni M, Calvani F, Catrambone F, Felicetti P, Gensini M, Terracciano R, Altamura M, Bressan A, Giuliani S, Maggi CA, Meini S, Valenti C, and Quartara L

Subjects
Animals, Bradykinin metabolism, Bronchoconstrictor Agents chemical synthesis, Bronchoconstrictor Agents chemistry, Bronchoconstrictor Agents pharmacology, CHO Cells, Cricetinae, Cricetulus, Crystallography, X-Ray, Drug Design, Guinea Pigs, Humans, Hypotension chemically induced, Inositol Phosphates biosynthesis, Models, Molecular, Molecular Structure, Piperazine, Piperazines chemistry, Quinolines chemistry, Quinolines pharmacology, Radioligand Assay, Receptor, Bradykinin B2 metabolism, Sarcosine chemical synthesis, Sarcosine chemistry, Sarcosine pharmacology, Structure-Activity Relationship, Sulfonamides chemistry, Sulfonamides pharmacology, Bradykinin B2 Receptor Antagonists, Quinolines chemical synthesis, Sarcosine analogs & derivatives, Sulfonamides chemical synthesis
Abstract

We recently published the extensive in vivo pharmacological characterization of MEN 16132 (J. Pharmacol. Exp. Ther. 2005, 616-623; Eur. J. Pharmacol. 2005, 528, 7), a member of the sulfonamide-containing human B(2) receptor (hB(2)R) antagonists. Here we report, in detail, how this family of compounds was designed, synthesized, and optimized to provide a group of products with subnanomolar affinity for the hB(2)R and high in vivo potency after topical administration to the respiratory tract. The series was designed on the basis of indications from the X-ray structures of the key structural motifs A and B present in known antagonists and is characterized by the presence of an alpha,alpha-dialkyl amino acid. The first lead (17) of the series was submitted to extensive chemical work to elucidate the structural requirements to increase hB(2) receptor affinity and antagonist potency in bioassays expressing the human B(2) receptor (hB(2)R). The following structural features were selected: a 2,4-dimethylquinoline moiety and a piperazine linker acylated with a basic amino acid. The representative lead compound 68 inhibited the specific binding of [(3)H]BK to hB(2)R with a pKi of 9.4 and antagonized the BK-induced inositolphosphate (IP) accumulation in recombinant cell systems expressing the hB(2)R with a pA(2) of 9.1. Moreover, compound 68 when administered (300 nmol/kg) intratracheally in the anesthetized guinea pig, was able to significantly inhibit BK-induced bronchoconstriction for up to 120 min after its administration, while having a lower and shorter lasting effect on hypotension.

Published
2006
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5. Influence of lipophilicity on the biological activity of cyclic pseudopeptide NK-2 receptor antagonists.

Author

Quartara L, Fabbri G, Ricci R, Patacchini R, Pestellini V, Maggi CA, Pavone V, Giachetti A, and Arcamone F

Subjects
Alkylation, Amino Acid Sequence, Animals, Biological Assay, Chromatography, High Pressure Liquid, Cricetinae, Cyclization, Male, Mesocricetus, Molecular Sequence Data, Peptides chemistry, Peptides, Cyclic pharmacology, Pulmonary Artery metabolism, Rabbits, Structure-Activity Relationship, Trachea metabolism, Lipid Metabolism, Peptides pharmacology, Peptides, Cyclic chemical synthesis, Receptors, Neurokinin-2 antagonists & inhibitors
Abstract

A series of cyclic pseudopeptides of the formula cyclo(Leu psi[CH2NH]Xaa-Gln-Trp-Phe-beta Ala), where Xaa represents the residue of an alpha-amino acid, has been synthesized in order to establish the role of the Xaa side chain for tachykinin NK-2 receptor antagonist activity. Syntheses have been carried out in solid phase with either Fmoc or Boc strategy. The antagonist potency on NK-2 receptors in the hamster isolated trachea (HT) and the rabbit isolated pulmonary artery (RPA) bioassays increases with Xaa lipophilicity; cyclo(Leu psi[CH2NH]Cha-Gln-Trp-Phe-beta Ala) and cyclo(Leu psi[CH2NH]Asp(NHBzl)-Gln-Trp-Phe-beta Ala) resulted in being the two most active antagonists (pA2 = 9.06 and 9.26 on HT, respectively). A significant linear correlation was found between pA2 values determined in HT and RPA bioassays and capacity factors measured in reversed phase HPLC. The comparison between the biological activities of cyclic hexapeptides containing or not containing the aminomethylene moiety proved the crucial role of the pseudopeptide bond for determining high antagonist potency at the NK-2 receptor.

Published
1994
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