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C A Maggi

Publications and source records attributed to C A Maggi.

608 records · Page 34Linked to original sources
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

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

2,6-Diketopiperazines from amino acids, from solution-phase to solid-phase organic synthesis.

A method to prepare 1,3-disubstituted 2,6-diketopiperazines (2,6-DKP) as useful heterocyclic library scaffolds in the search of new leads for drug discovery is described. The method can be used in solution-phase and solid-phase conditions. In the key step of the synthesis, the imido portion of the new molecule is formed in solution through intramolecular cyclization, under basic conditions, of a secondary amide nitrogen on a benzyl ester. A Wang resin carboxylic ester is used as the acylating agent under solid-phase conditions, allowing the cyclization to take place with simultaneous cleavage of the product from the resin ("cyclocleavage"). The synthetic method worked well with several couples of amino acids, independently from their configuration, and was used for the parallel synthesis of a series of fully characterized compounds. The use of iterative conditions in the solid phase (repeated addition of fresh solvent and potassium carbonate to the resin after filtering out the product-containing solution) allowed us to keep diastereoisomer content below the detection limit by HPLC and (1)H NMR (200 MHz).

Amino Acids↗
PubMedDate not supplied

Pharmacology of MEN 11467: a potent new selective and orally- effective peptidomimetic tachykinin NK(1) receptor antagonist.

We have investigated the pharmacological properties of MEN 11467, a novel partially retro-inverse peptidomimetic antagonist of tachykinin NK(1) receptors. MEN 11467 potently inhibits the binding of [(3)H] substance P (SP) to tachykinin NK(1) receptors in the IM9 limphoblastoid cell line (pK(i) = 9.4 +/- 0.1). MEN 11467 is highly specific for the human tachykinin NK(1) receptors, since it has negligible effects (pK(i) <6) on the binding of specific ligands to tachykinin NK(2) or NK(3) receptors and to a panel of 30 receptors ion channels unrelated to tachykinin receptors. The antagonism exerted by MEN 11467 at tachykinin NK(1) receptors is insurmountable in saturation binding experiments, both K(D) and B(max) of SP were significantly reduced by MEN 11467 (0.3-10 nM). In the guinea-pig isolated ileum, MEN 11467 (0.03-1 nM) produced a nonparallel rightward shift of the concentration-response curve to SP methylester with a concomitant reduction of the Emax to the agonist (pK(B) = 10.7 +/- 0.1). Moreover the antagonist activity of MEN 11467 was hardly reversible despite prolonged washout. In vivo, MEN 11467 produced a long lasting (> 2-3h) dose-dependent antagonism of bronchoconstriction induced by the selective tachykinin NK(1) receptor agonist, [Sar(9), Met(O(2))(11)]SP in anaesthetized guinea-pigs (ID(50)s' = 29+/-5, 31+/-12 and 670+/-270 microg/kg, after intravenous, intranasal and intraduodenal administration, respectively), without affecting bronchoconstriction induced by methacholine. After oral administration MEN 11467 produced a dose-dependent inhibition of plasma protein extravasation induced in guinea-pig bronchi by [Sar(9), Met(O(2))(11)] (ID(50) = 6.7 +/- 2 mg/kg) or by antigen challenge in sensitized animals (ID(50) = 1.3 mg/kg). After i.v. administration MEN 11467 weakly inhibited the GR 73632-induced foot tapping behaviour in gerbil (ED(50) = 2.96 +/- 2 mg/kg), indicating a poor ability to block central tachykinin NK(1) receptors. These results demonstrate that MEN 11467 is a potent, highly selective and orally effective insurmountable pseudopeptide antagonist of peripheral tachykinin NK(1) receptors with a long duration of action.

Administration, Oral↗
PubMedDate not supplied

Activation of capsaicin-sensitive primary afferents in the rat urinary bladder by compound 48/80: a direct action on sensory nerves?

We have assessed the ability of compound 48/80, a mast cell degranulating agent, to activate the sensory and efferent function of capsaicin-sensitive primary afferents in the rat urinary bladder. Compound 48/80 produced a calcium-dependent release of calcitonin gene-related peptide-like immunoreactivity from the superfused rat urinary bladder. This effect was prevented by in vitro capsaicin desensitization, but was not affected by indomethacin, methysergide, ondansetron, chlorpheniramine or cimetidine, nor by systemic pretreatment with compound 48/80 at a dose regimen which prevented lethality produced by intravenous administration of it in anesthetized rats. Compound 48/80 also produced a contraction of the rat isolated bladder which was not reduced by methysergide, indomethacin or in vitro capsaicin desensitization. In vivo, topical application of compound 48/80 on the serosal surface of the rat urinary bladder activated a series of high amplitude rhythmic bladder contractions which were hexamethonium-sensitive (micturition reflex). This effect was prevented by systemic capsaicin desensitization while it was unchanged by chlorpheniramine, methysergide, indomethacin or ondansetron. Administered intravenously, compound 48/80 produced a plasma protein extravasation (Evans blue leakage technique) in the rat urinary bladder which was abolished by systemic capsaicin pretreatment or chlorpheniramine while it was unaffected by methysergide or indomethacin. The present findings provide direct neurochemical evidence that compound 48/80 activates the peripheral endings of capsaicin-sensitive primary afferent neurons, leading to a stimulation of their sensory and efferent functions in the rat urinary bladder. The possibility of a direct action of compound 48/80 in producing excitation of capsaicin-sensitive sensory nerves should be considered.

Animals↗
PubMedDate not supplied

Tachykinin receptors and receptor subtypes.

The tachykinins, substance P, neurokinin A and neurokinin B, are a family of neuropeptides widely distributed in the mammalian central and peripheral nervous system. In the peripheral nervous system, tachykinins released from peripheral endings of sensory nerves are responsible for the neurogenic inflammation phenomenon. In the spinal cord/central nervous system, tachykinins play a role in pain transmission/perception and in some autonomic reflexes and behaviors. Their actions are mediated by three distinct receptors, termed NK1, NK2 and NK3. All tachykinin receptors belong to the superfamily of G protein-coupled receptors, with seven putative transmembrane spanning segments. In the past few years, a number of potent and selective antagonists, of both peptide and nonpeptide nature, has been developed for the NK1, NK2 and NK3 receptors. The contemporary isolation and cloning of the three tachykinin receptors enable now to study the molecular determinants for the interaction of natural tachykinins with their receptors, and the mechanism by which the antagonists interfere in this process. Furthermore, the introduction of tachykinin antagonists has revealed a striking species-related heterogeneity among the tachykinin receptors, and has also suggested a possible intra-species heterogeneity for both NK1 and NK2 receptors. However, molecular biology studies are needed to prove the existence of true tachykinin receptor subtypes.

Amino Acid Sequence↗