[show abstract][hide abstract] ABSTRACT: A series of 4-substituted piperazine derivatives bearing a norbornene nucleus have been prepared and their affinity for serotonin 5-HT1A, 5-HT2A and 5-HT2C receptors has been evaluated. Compounds showing the highest affinity have been selected and evaluated on dopaminergic (D1 and D2) and adrenergic (alpha1 and alpha2) receptors. The combination of structural elements (heterocyclic nucleus, oxyalkyl chain and 4-substituted piperazine) known to be critical in order to have affinity on serotonin receptors and the proper selection of substituents led to compounds with higher receptor specificity and affinity. In binding studies, several molecules showed affinity in nanomolar range towards 5-HT1A, 5-HT2A and 5-HT2C receptors and moderate to no affinity for other relevant receptors (D1, D2, alpha1 and alpha2). Compound 2q 4-[2-[4-(3,4-dichlorophenyl)piperazin-1-yl]ethoxy]-4-aza-tricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (Ki = 1.13 nM), was the most active and selective derivative for the 5-HT2C receptor with respect to other serotonin, dopaminergic and adrenergic receptors. Moreover, compound 3p showed mixed 5-HT2A/5-HT2C activity with affinity values in nanomolar range.
[show abstract][hide abstract] ABSTRACT: Several studies have been published on discovering involvement of PARs receptors in a number of disease states, including cancer and inflammation of the cardiovascular, respiratory, musculoskeletal, gastrointestinal and nervous systems. This mini-review will focus on recent advances in the synthesis of PAR ligands highlighting their therapeutic potential in the treatment of various inflammatory diseases.
Mini Reviews in Medicinal Chemistry 07/2009; 9(6):653-63. · 2.87 Impact Factor
[show abstract][hide abstract] ABSTRACT: Irritable bowel syndrome (IBS) is characterized by dysfunction of the afferent pathways that may lead to visceral hypersensitivity. Trimebutine is a weak opioid receptor agonist used in the treatment of IBS. We report on the effects of a novel derivative in which trimebutine has been salified with nitro-arginine(NO2-Arg-Trim), in modulating nociception to colorectal distension (CRD) in intact and post-colitis rats,an animal model that mimics some features of IBS. Colorectal sensitivity and pain were assessed by measuring the abdominal withdrawal score (AWR) during CRD. Healthy rats were treated with vehicle,trimebutine (10 mg/kg i.p.) or NO2-Arg-Trim (4, 8 and 16 mg/kg i.p.). Post-colitis, allodynic rats were investigated 4 weeks after colitis induction. Treating healthy rats with NO2-Arg-Trim resulted in a dose-dependent attenuation of CRD-induced nociception and in an inhibition of CRD-induced overexpression of spinal cFOS mRNA. NO2-Arg-Trim-induced antinociception was reversed by the opioid receptor antagonist naloxone and by the NO synthase-cGMP pathway inhibitor methylene blue, while L-NAME had no effect.The antinociceptive effect of NO2-Arg-Trim was maintained in a rodent model of post-inflammatory allodynia. In this setting,NO2-Arg-Trim but not trimebutine, significantly down-regulated the spinal cFOS mRNA expression and increased blood concentrations of NO2 +NO3. Moreover, the expression of several genes involved in inflammation and pain, as IL-1beta, TNFalpha, COX2 and iNOS, was up-regulated in colonic tissue from post-colitis rats and NO2-Arg-Trim, but not trimebutine, effectively reversed this effect. In summary, these data suggest that NO2-Arg-Trim inhibits nociception induced by CRD in both healthy and post-colitis, allodynic rats. The NO2-arginine moiety interacts with the opioid agonist trimebutine to potentiate its analgesic activity. This study provides evidence that NO2-arginine derivative of trimebutine might have beneficial effect in the treatment of painful intestinal disorders.
Pharmacological Research 06/2009; 59(5):319-29. · 4.35 Impact Factor
[show abstract][hide abstract] ABSTRACT: The interest in the microwave assisted organic synthesis has been growing during the recent years. It results from an increasing knowledge of fundamentals of the dielectric heating theory, availability of an equipment designed especially for the laboratory use as well as the discovery of the special techniques of the microwave syntheses. The efficiency of microwave flash-heating chemistry in dramatically reducing reaction times (reduced from days and hours to minutes and seconds) has recently been proven in several different fields of organic chemistry and this aspect is of great importance in high-speed combinatorial and medicinal chemistry. In this contribution, the current state of the art is summarized providing examples of the most recent applications in the field of microwave assisted synthesis of biologically active compounds both in heterocyclic and in peptide and peptidomimetic optimization.
Mini Reviews in Medicinal Chemistry 04/2009; 9(3):340-58. · 2.87 Impact Factor
[show abstract][hide abstract] ABSTRACT: In this paper, we describe the synthesis of conformationally constrained dipeptide mimetic derivatives. Microwave flash heating was used in several synthetic steps providing the opportunity to perform the reactions in dramatically shortened time as well as to increase the obtained yields. The efficiency of the methodology makes it useful in order to prepare other dipeptides containing the 4-amino-tetrahydro-2-benzazepin-3-one motif.
[show abstract][hide abstract] ABSTRACT: Protease-activated receptor-1 (PAR-1) is a G-coupled receptor activated by alpha-thrombin and other proteases. In this paper we describe the synthesis and the pharmacological evaluation of novel peptide-mimetic antagonists (compounds 1-16) characterized by the presence of new heterocyclic nuclei such as 2-methyl-indole (5- and 6-substituted) and 1,4-benzodiazepine moiety. The new derivatives, tested in order to evaluate their antagonist potency by using human platelet aggregation induced by PAR-1AP, resulted in some cases (compounds 1 and 4) more potent than the reference. The compounds, tested on aortic rings, confirmed the results obtained in the aggregation assay.
[show abstract][hide abstract] ABSTRACT: The 5-[2-ethoxy-5-(4-methylpiperazin-1-ylsulfonyl)phenyl]-1-methyl-3-propyl-1,6-dihydro-7 H-pyrazolo[4,3-d]pyrimidin-7-one, sildenafil, is a cGMP-specific phosphodiesterase-5 (PDE5) inhibitor used for penile erectile dysfunction. In the search for more potent and selective PDE5 inhibitors, new sildenafil analogues (6a-v), characterized by the presence on the sulfonyl group in the 5' position of novel N-4-substituted piperazines or ethylenediamine moiety, were prepared by traditional and microwave-assisted synthesis and tested in rabbit isolated aorta and corpus cavernosum. Similarly to sildenafil, several analogues showed IC50 values in the nanomolar range. In the in vitro studies, all the tested compounds caused concentration-dependent relaxations in both rabbit isolated aorta and corpus cavernosum. All sildenafil analogues potentiated the nitric oxide-dependent vasodilation in endothelium-intact rabbit aorta. Compound 6f exhibited great pEC50 value in corpus cavernosum, and compounds 6r and 6u in isolated aorta were found as potent as sildenafil for inhibiting PDE5. Because several analogues were significantly more lipophilic than sildenafil, these compounds may offer a new lead for development of new sildenafil analogues.
Journal of Medicinal Chemistry 06/2008; 51(9):2807-15. · 5.61 Impact Factor
[show abstract][hide abstract] ABSTRACT: Increase of VPAC receptor s binding to the (16)gamma-glutamyl diaminopropane vasoactive intestinal peptide (VIP-DAP) agonist, a vasoactive intestinal polypeptide (VIP) structural analogue containing a positive charge at position 16, has confirmed the importance of a positive charge at this site. By investigating the effect of distance from the peptide backbone Calpha of a positive charge in position 16, data are reported here concerning: (i) a novel chemical method used for the synthesis of a new family of (16)gamma-glutamyl diamine VIP derivatives differing among them for single carbon atoms and including diaminoethane (VIP-DAE2), diaminopropane (VIP-DAP3), diaminobutane (VIP-DAB4), diaminopentane (VIP-DAP5), and diaminohexane (VIP-DAH6); (ii) functional characterization of these compounds on human VPAC1 and VPAC2 receptors. In more detail, the EC50 and IC50 values, when measured as a function of the alkylic chain length, show in more detail, that the use of VIP-DAB4 derivative changes the IC50 but not the EC50, thus indicating on hVPAC2 receptor an unexpected relationship between binding and activity that differs from that obtained on hVPAC1.
Journal of Peptide Science 02/2008; 14(1):102-9. · 2.07 Impact Factor
[show abstract][hide abstract] ABSTRACT: This paper reports the microwave-assisted synthesis and the binding assays on the 5-HT1A, 5-HT2A and 5-HT2C receptors of new benzotriazinone derivatives, in order to identify selective ligands for the 5-HT1A subtype receptor. Conventional and microwave heating of the reactions were compared. Good yields and short reaction times are the main advantages of our synthetic route. More active compounds were selected and further evaluated for their binding affinities on D1, D2 dopaminergic and α1, α2 adrenergic receptors. The 3-(2-(4-(naphthalen-1-yl)piperazin-1-yl)ethyl)benzo[d][1,2,3]triazin-4(3H)-one 5 with Ki = 0.000178 nM was the most active and selective derivative for the 5-HT1A receptor with respect to other serotonin receptors and the most selective derivative compared to dopaminergic and adrenergic receptors.
[show abstract][hide abstract] ABSTRACT: We report microwave-assisted synthetic routes, the pharmacokinetic profile along with results from ulcerogenicity and mutagenicity studies of atenolol aspirinate, and an already described derivative, in which acetyl salicylic acid (aspirin) was connected to atenolol by an ester linkage. Atenolol aspirinate was stable towards aqueous hydrolysis but rapidly hydrolyzed in plasma (t(1/2) = 7.6 min). The results showed that the rapid and complete hydrolysis generates atenolol salicylate, which assumes a conformation stabilized by two intramolecular H-bonds, avoiding its further hydrolysis to salicylic acid and atenolol.
Archiv der Pharmazie 10/2007; 340(9):445-55. · 1.54 Impact Factor
[show abstract][hide abstract] ABSTRACT: Peptide T (ASTTTNYT), a segment corresponding to residues 185-192 of gp120, the coat protein of HIV, has several important biological properties in vitro that have stimulated the search for simpler and possibly more active analogs. We have previously shown that pseudocyclic hexapeptide analogs containing the central residues of peptide T retain considerable chemotactic activity. We have now extended the design of this type of analogs to peptides containing different aromatic residues and/or Ser in lieu of Thr. The complex conformation-activity relationship of these analogs called for a reexamination of the basic conformational tendencies of peptide T itself. Here, we present an exhaustive NMR conformational study of peptide T in different media. Peptide T assumes a gamma-turn in aqueous mixtures of ethylene glycol, a type-IV beta-turn conformation in aqueous mixtures of DMF, and a type-II beta-turn conformation in aqueous mixtures of DMSO. The preferred conformations for the analogs were derived from modeling, starting from the preferred conformations of peptide T. The best models derived from the gamma-turn conformation of peptide T are those of peptides XII (DSNYSR), XIII (ETNYTK) and XVI (ESNYSR). The best models derived from the type-IV beta-turn conformation of peptide T are those of peptides XIV (KTTNYE) and XV (DSSNYR). No low-energy models could be derived starting from the type-II beta-turn conformation of peptide T. The analogs with the most favored conformations are also the most active in the chemotactic test.
Journal of Peptide Science 07/2007; 13(6):413-21. · 2.07 Impact Factor
[show abstract][hide abstract] ABSTRACT: Galanthamine is an alkaloid approved for the treatment of Alzheimer's disease. In this paper the syntheses and the anticholinesterase activities of new glucosyl and nitroxy derivatives substituted on position 6 are reported. Compounds 2, 3 and 5 presented a percentage of inhibition of 35.22%, 47.48% and 67.89% respectively.
[show abstract][hide abstract] ABSTRACT: 1,3 Dipolar cycloaddition of Fmoc-amino azides and acetylenic amides produces under solvent free irradiation a mixture of 1,4 or 1,5 substituted [1,2,3]-triazoles. The presence of copper (I) iodide, plays a central role on regioselectivity. Four Fmoc-amino azides characterized by different steric hindrance in side chains, and three different terminal alkynes, provided only the 1,4 substituted regioisomer under thermal microwave heating. Good yields, low consumption of organic solvents and short reaction times are the main aspects of our procedure. Reactions are compared to regioselective copper (I) catalysed solution synthesis performed at room temperature.
[show abstract][hide abstract] ABSTRACT: Mesalamine is the first-line therapy for colitis, but it lacks potency and is only effective for mild-to-moderate forms of this disease. Hydrogen sulphide has been shown to be a potent, endogenous anti-inflammatory substance, modulating leukocyte-endothelial adhesion and leukocyte migration. The purpose of this study was to determine if an H(2)S-releasing derivative of mesalamine (ATB-429) would exhibit increased potency and effectiveness in a mouse model of colitis.
Colitis was induced in mice with trinitrobenzene sulphonic acid and the effects of ATB-429 and mesalamine were compared in several treatment regimens. The severity of colitis was determined using several indices, including a disease activity score (comprised of scores for diarrhea, weight loss and fecal blood), colonic myeloperoxidase activity and macroscopic/microscopic scoring of tissue injury.
Irrespective of the treatment regiment, ATB-429 was more effective than mesalamine in reducing the severity of colitis. ATB-429 was particularly effective in reducing granulocyte infiltration into the colonic tissue (by approximately 70%), as well as reducing the expression of mRNA for several key proinflammatory cytokines/chemokines (e.g., TNFalpha, IFNgamma). Treatment with ADT-OH, the H(2)S-releasing moiety of ATB-429, did not affect severity of colitis.
ATB-429 exhibits a marked increase in anti-inflammatory activity and potency in a murine model of colitis, as compared to mesalamine. These results are consistent with recently described anti-inflammatory effects of H(2)S. ATB-429 may represent an attractive alternative to mesalamine for the treatment of inflammatory bowel disease.
British Journal of Pharmacology 05/2007; 150(8):996-1002. · 5.07 Impact Factor
[show abstract][hide abstract] ABSTRACT: Gastrointestinal damage caused by nonsteroidal anti-inflammatory drugs (NSAIDs) remains a significant clinical problem. Hydrogen makes an important contribution to mucosal defense, and NSAIDs can suppress its synthesis. In this study, we evaluated the gastrointestinal safety and anti-inflammatory effects of a novel "HS-NSAID" (ATB-337) that consists of diclofenac linked to a hydrogen sulfide-releasing moiety.
The gastrointestinal injury-inducing effects of single or repeated administration of diclofenac versus ATB-337 were compared in rats, as were their effects on prostaglandin synthesis and cyclooxygenase-1 and -2 activities. The ability of these drugs to reduce carrageenan-induced paw edema and to elicit leukocyte adherence to the vascular endothelium (intravital microscopy) were also examined in rats.
Diclofenac (10-50 micromol/kg) dose-dependently damaged the stomach, while ATB-337 did not. Repeated administration of diclofenac caused extensive small intestinal damage and reduced hematocrit by 50%. ATB-337 induced >90% less intestinal damage and had no effect on hematocrit. Diclofenac, but not ATB-337, elevated gastric granulocyte infiltration and expression of tumor necrosis factor alpha, lymphocyte function-associated antigen 1, and intercellular adhesion molecule 1. ATB-337 inhibited cycloxygenase-1 and cyclooxygenase-2 activity as effectively as diclofenac. ATB-337 did not induce leukocyte adherence, whereas diclofenac did, and was more potent at reducing paw edema.
An HS-NSAID spares the gastric mucosa of injury despite markedly suppressing prostaglandin synthesis. This effect may be related to hydrogen sulfide-mediated inhibition of tumor necrosis factor-alpha expression and of the leukocyte adherence to vascular endothelium normally induced by cyclooxygenase inhibitors.
[show abstract][hide abstract] ABSTRACT: A recombinant dengue 2 virus NS2B-NS3 protease (NS means non-structural virus protein) was compared with human furin for the capacity to process short peptide substrates corresponding to seven native substrate cleavage sites in the dengue viral polyprotein. Using fluorescence resonance energy transfer peptides to measure kinetics, the processing of these substrates was found to be selective for the Dengue protease. Substrates containing two or three basic amino acids (Arg or Lys) in tandem were found to be the best, with Abz-AKRRSQ-EDDnp being the most efficiently cleaved. The hydrolysis of dipeptide substrates Bz-X-Arg-MCA where X is a non-natural basic amino acid were also kinetically examined, the best substrates containing aliphatic basic amino acids. Our results indicated that proteolytic processing by dengue NS3 protease, tethered to its activating NS2B co-factor, was strongly inhibited by Ca2+ and kosmotropic salts of the Hofmeister's series, and significantly influenced by substrate modifications between S4 and S6'. Incorporation of basic non-natural amino acids in short peptide substrates had significant but differential effects on Km and k(cat), suggesting that further dissection of their influences on substrate affinity might enable the development of effective dengue protease inhibitors.
Archives of Biochemistry and Biophysics 02/2007; 457(2):187-96. · 3.37 Impact Factor
[show abstract][hide abstract] ABSTRACT: Three series of compounds characterized by biphenylic structure were synthesized in order to develop new scaffolds able to induce β-sheet folding in the peptides. Microwave flash heating was used in order to shorten reaction times and to enhance the obtained yields. Simulated annealing molecular dynamics simulations demonstrated that some of the compounds were capable of adopting a 15-membered intramolecularly hydrogen-bonded conformation, which supports an antiparallel β-sheet structure.Graphical abstract