Biomedical subjects

P Rovero

Publications and source records attributed to P Rovero.

101 records · Page 6Linked to original sources

PubMedDate not supplied

Structure-activity studies of neurokinin A.

A structure-activity study on neurokinin A and its C-terminal fragment NKA (4-10) has been performed in order to find selective agonists for the NK-2 receptor and identify chemical modifications suitable for protecting the peptides from degradation, while maintaining activity. Five series of compounds have been prepared and tested: 1. the complete series of the L-Ala monosubstituted analogues of NKA; 2. a series of NKA fragments from the C- or N-terminal; 3. the complete series of NKA (4-10) analogues monosubstituted with beta-Ala; 4. a series of NKA (4-10) analogues with monosubstitutions in pos. 4, 8, 10 or multisubstitutions in two or more of the same positions; and 5. a series of 6 NKA (4-10) analogues monosubstituted with 1-amino,1-cyclohexane carboxylic acid residue. It has been found that the most selective agonists for the NK-2 receptor system are [beta Ala8]NKA (4-10) and [Nle10]NKA (4-10). Protection from aminopeptidase may be obtained by acetylation of the N-terminal amide of NKA (4-10), while partial protection from endopeptidases should be expected from the presence of beta-Ala in position 8. Conformational constraints induced with 1,amino,1-cyclohexane carboxylic acid residue gave weakly active compounds. Multiple substitutions reduce rather than potentiating the favorable effects of the corresponding monosubstituted compounds.

Animals↗

PubMedDate not supplied

Tachykinins protect against ethanol-induced gastric lesions in rats.

Subcutaneous pretreatment of rats with neurokinin (NK) A or the fragment NKA(4-10) reduced the degree of gastric lesions induced by oral administration of 96% ethanol. The protective effect of NKA(4-10) was dose-dependent. Arg-NKB, the water soluble derivative of NKB, was less effective than NKA or NKA(4-10) while [Me-Phe7]NKB, substance P (SP) and SP-methyl-ester were inactive. The NKA(4-10) antilesion effect was reversed by pretreatment with N-ethyl-maleimide, suggesting a possible involvement of sulphydryls in its action. Among the nonmammalian tachykinins, kassinin significantly reduced ethanol-induced lesions while eledoisin and physalaemin at equivalent molar doses were inactive. These results provide, for the first time, evidence that tachykinins and their derivatives exert gastroprotective activity toward ethanol-induced haemorrhagic lesions. Assuming a receptor-mediated mechanism, NK-2 sites could be involved.

Animals↗

PubMedDate not supplied

A potent and selective agonist for NK-2 tachykinin receptor.

Replacement of the glycine in position 8 of the C-terminal heptapeptide NKA(4-10) with beta-alanine give rise to a potent and selective agonist for the NK-2 tachykinin receptor. The affinity of [beta-Ala8]-NKA(4-10) to the NK-2 receptor is enhanced by almost one order of magnitude as compared to NKA(4-10), while affinity decreases at about the same extent at NK-1 and NK-3 receptors, respectively. Synthesis and biological activities of a series of NKA(4-10) analogues systematically replaced in each position with beta-alanine are also reported.

Alanine↗

PubMedDate not supplied

Synthesis and biological activity of NK-2 selective tachykinin antagonists containing D-tryptophan.

By introducing D-Trp in position 6 and 8 along with pyroglutamic acid (Pyr) in position 4 or Nle in position 10 of NKA(4-10) we have obtained selective although weak NK-2 tachykinin receptor antagonists. Similar substitutions, previously reported on the sequence of SP, gave rise to nonselective antagonists presumably for the limited selectivity of the agonist used as template. Further modifications like the addition of a third D-Trp in position 9 gave rise to more potent but less selective antagonists, thus showing that each amino acid substitution can dramatically affect selectivity.

Amino Acid Sequence↗

PubMedDate not supplied

Analogs of neurokinin A(4-10) afford protection against gastroduodenal ulcers in rats.

We have developed a novel series of peptides, related to the NKA(4-10) sequence, in which substitution of selected amino acids determined variations in the affinity for the TK receptor subtypes. Subcutaneous pretreatment of rats with some peptides of this series reduced gastric ulcers induced by ethanol, indomethacin or acetylsalicylic acid (ASA) as well as duodenal ulcers induced by dulcerozine. In particular [Ala5]NKA(4-10) and [Ala5,beta Ala8]NKA(4-10) possess a broad spectrum of antiulcer activity which is long lasting and stronger than the precursor NKA(4-10). The observation that the prevention of ethanol-induced gastric lesions could be reversed by pretreatment with indomethacin favors the possible involvement of prostaglandins in the observed gastroprotection by TK analogs.

Amino Acid Sequence↗

PubMedDate not supplied

Role of D-tryptophan for affinity of MEN 10207 tachykinin antagonist at NK2 receptors.

The role of the D-Trp residues in the sequence of the NK2-selective tachykinin antagonist, MEN 10207 (Asp-Tyr-D-Trp-Val-D-Trp-D-Trp-Arg-NH2). has been examined by replacement of each D-Trp with either the L-isomer or the residue naturally occurring in the same position of neurokinin A(4-10). The biological activity of the analogues thus obtained has been characterized, with special attention to the selectivity for the three tachykinin receptors and for the two subtypes of the NK2 receptor recently described. We conclude that the simultaneous presence of the three D-Trp residues of MEN 10207 is crucial both for affinity and for selectivity.

Amino Acid Sequence↗

PubMedDate not supplied

CGRP antagonist activity of short C-terminal fragments of human alpha CGRP, CGRP(23-37) and CGRP(19-37).

The activity of short C-terminal fragments of human alpha calcitonin gene-related peptide (CGRP), CGRP(19-37), and CGRP(23-37), and of the N-terminally acetylated (Ac) derivative, AcCGRP(19-37), has been investigated in the guinea pig isolated left atria (electrically driven) for their ability to antagonize the positive inotropic effect of human alpha CGRP. All the peptides tested produced a rightward displacement of the curve to the agonist without depressing the maximal response: apparent pA2 values were 5.39 and 4.81 for CGRP(19-37) and CGRP(23-37), respectively, as compared to 6.81 for CGRP(8-37). AcCGRP(19-37) was a more potent antagonist than the parent peptide, with an apparent pA2 value of 6.03.

Animals↗

PubMedDate not supplied

Structure-activity study of the C-terminal residue of MEN 10207 tachykinin antagonist.

The role of the C-terminal residue in the sequence of the NK-2-selective tachykinin antagonist, MEN 10207 (Asp-Tyr-D-Trp-Val-D-Trp-D-Trp-Arg-NH2), has been examined by systematic amino acid substitutions. Biological activity has been measured on two in vitro preparations chosen as paradigms of the recently described NK-2 receptor subtypes, namely the rabbit pulmonary artery and the hamster trachea, in order to define the structural requirements necessary for antagonist subtype selectivity. We conclude that in the presence of a C-terminal hydrophilic residue, affinity is maximal for the NK-2A subtype, while hydrophobic, bulky and aromatic residues increase affinity for the NK-2B subtype.

Amino Acid Sequence↗

PubMedDate not supplied

Toward the rational development of peptidomimetic analogs of the C-terminal endothelin hexapeptide: development of a theoretical model.

In an early report on the structure-activity relationship of endothelin (ET) peptides, it was reported that the C-terminal hexapeptide ET(16-21), His-Leu-Asp-Ile-Ile-Trp, is the minimum ET fragment which maintains biological activity in some, but not all the tissues responding to ETs. Subsequently, other authors described a series of analogs of this peptide, in which the His 16 residue was replaced by non-natural amino acids, characterized by bulky aromatic side chains. Among them, two well-characterized non-selective ETA/ETB antagonists were PD 142893 and PD 145065; interest in these potent ET antagonists was, however, reduced by their peptidic structure which was likely to lead to undesirable properties such as poor bioavailability and short duration of action. On the basis of these premises, our previous studies led to the development of a peptidomimetic ligand of ET receptors (compound 3), based on the replacement of the His 16 residue of ET(16-21) with an (E)-N-(benzyloxy)iminoacyl moiety; compound 3 proved to possess a certain affinity for ET receptors, albeit lower than that shown by PD 142893 and PD 145065. We report here on ETA/ETB binding affinity of compounds 4-12, designed as a new series of ET(16-21) analogs. Compounds 4 and 5 were practically devoid of any affinity; derivatives 6-12 exhibited appreciable affinity indices for ETB receptors higher than that shown by 3, even if still lower than that obtained for PD 145065. This paper also describes the development of a pharmacophoric model able to explain the ET receptor binding properties of our hexapeptide analogs compared with those of PD 142893 and PD 145065 and IRL2500, recently reported as a potent ETB selective endothelin antagonist.

Amino Acid Sequence↗

PubMedDate not supplied

Synthesis and biological activity of N-methylated analogues of neurokinin A.

Limited conformational constraints have been introduced in the sequence of the C-terminal heptapeptide NKA(4-10) by N-methylation of individual peptide bonds and the biological activities of the peptides thus obtained were evaluated on three in vitro preparations sensitive and quite selective for each of the naturally-occurring neurokinins, in order to assess the effect of N-methylation on receptor selectivity. The analogue methylated in position 7, namely [MeVal7] NKA(4-10) shows some selectivity for the NK-P receptor, while none of the tested compounds appear to be selective for the NK-A receptor.

Animals↗

PubMedDate not supplied

Binding of human GM-CSF to synthetic peptides of the alpha subunit of its receptor.

We have synthesized a series of peptides corresponding to portions of the extracellular domain of human granulocyte-macrophage colony stimulating factor receptor alpha subunit (hGM-CSFR alpha). The sequences were chosen according to the homology between hGM-CSFR alpha and the growth hormone receptor (GHR) and correspond to the regions reported to form the binding site of the latter receptor. The peptides were examined for their binding activity to hGM-CSF by affinity chromatography on resin-immobilized hGM-CSF and by a solid phase binding assay. For peptides endowed with hGM-CSF binding activity were identified and the postulated homology between the binding sites of hGM-CSFR alpha GHR was confirmed.

Amino Acid Sequence↗