86,703 research outputs found
Synthesis of 4-amino-6-(hetero)arylalkylamino-1,2,4-triazolo[4,3-a]quinoxalin-1-one derivatives as potent A(2A) adenosine receptor antagonists
No full textIn previous papers (Colotta, V. et al. Arch. Pharm. Pharm. Med. Chem. 1999, 332, 39. Colotta, V. et al. J. Med. Chem. 2000, 43, 1158) we reported the synthesis and binding affinity at bovine (b) A(1) and A(2A) and human (h) A(3) adenosine receptors (ARs) of the 4-amino-6-benzylamino-2-phenyl-1,2,4-triazolo[4,3-a]quinoxalin-1-one (compound A) which resulted in a potent and selective A(2A) AR antagonist. Compound A provided the lead compound of a series of 6- or 8-(hetero)arylalkylamino-4-amino-2-phenyl- 1,2,4-triazolo[4,3-a]quinoxatin-1-one derivatives (compounds 1-20) which are the object of this paper. Most of the newly synthesized compounds are inactive at hA(3) ARs while they possess both nanomolar bA(2A) affinities and different degrees of bA(2A) versus bA(1) selectivity. The binding data show that hydrophilic substituents on the benzyl moiety are the most profitable for bA(2A) receptor affinity. Furthermore, their steric hindrance seems to play an important role for the bA(2A) AR interaction, thus suggesting that the 6-aralkylamino moiety of these ligands interacts with a size-limited binding pocket of this AR subtype. Thus, the SAR studies provided us some new insights about the structural requirements of the bA(2A) AR recognition site. (C) 2003 Elsevier Ltd. All rights reserved
Synthesis and structure-activity relationships of a new set of 2-arylpyrazolo[3,4-c] quinoline derivatives as adenosine receptor antagonists
No full textIn a recent paper (Colotta et al. J. Med. Chem. 2000, 43, 1158-1164) we reported the synthesis and adenosine receptor binding activity of two sets of 2-aryl-1,2,4-triazolo[4,3-a] quinoxalines (A and B) some of which were potent and selective A(1) or A(3) antagonists. In this paper the synthesis of a set of 2-arylpyrazolo[3,4-c]quinolin-4-ones 1-10, 4-amines 11-18, and 4-amino-substituted derivatives 19-35 are reported. The binding activity at bovine A(1) and A(2A) and human cloned A(3) adenosine receptors showed that (i) the substituent on the appended 2-phenyl ring could be used to modulate A(1) and A(3) affinity, (ii) the 4-amino group was necessary for A(1) and A(2A) binding activity, and (iii) a nuclear or extranuclear C=O proton acceptor at position 4 yielded potent and selective A(3) antagonists. These results are in agreement with those of the previously reported series A and B suggesting a similar adenosine receptor binding mode. In particular, the A(3) nanomolar affinity of 1-8, 31-33, and 35 confirms the hypothesis of the presence in the N-6 region of the adenosine A(3) subtype of a proton donor able to bind to a C=O proton acceptor at position 4
Modulation of granulocyte survival and programmed cell death by cytokines and bacterial products
No full textSynthesis and structure-activity relationships of a new set of 1,2,4-triazolo[4,3-a]quinoxalin-1-one derivatives as adenosine receptor antagonists
No full textIn a previous paper (Colotta V. et al., J. Med. Chem. 2000, 43, 1158), we reported the synthesis and the binding activity of some 4-oxo (A) and 4-amino (B) substituted 1,2,4-triazolo[4,3-a]quinoxalin-1-ones, bearing different substituents on the appended 2-phenyl ring (region 1), some of which were potent and selective A(1) or A(3) antagonists. To further investigate the SAR in this class of antagonists, in the present paper some 2-phenyl-1,2,4-triazolo[4,3-a]quinoxalin-1-one derivatives of both series A and B, bearing simple substituents on the benzofused moiety (region 2), are reported. The binding data at bovine A(1) (bA(1)) and A(2A)(bA(2A)) and at human A(3) (hA(3)) adenosine receptors (ARs) show that in series A (compounds 1, 4-11) the presence of substituents on the benzofused moiety is, in general, not advantageous for anchoring at all three AR subtypes, while within series B (compounds 12-21) it exerts a beneficial effect for both bA(1) and hA(3) AR affinities which span the low nanomolar range. In particular, among the 4-amino derivatives 12-21, the 8-chloro-6-nitro (compound 17) and the 6-nitro (compound 18) substitutions afford, respectively, the highest bA(1) and hA(3) AR affinity. Moreover, compound 18, additionally investigated in binding assays at human A(1) (hA(1)) receptors, shows a 183-fold selectivity for hA(3) versus hA(1) receptors. Finally, the SAR studies provide some new insights about the steric and lipophilic requirements of the hA(3) receptor binding pocket which accommodates the benzofused moiety of our 4-amino-triazoloquinoxalin-1-one derivatives. (C) 2003 Elsevier Ltd. All rights reserved
1,2,4-Triazolo[4,3-a]quinoxalin-1-one: a versatile tool for the synthesis of potent and selective adenosine receptor antagonists
No full text4-Amino-6-benzylamino-1,2-dihydro-2-phenyl-1,2,4-triazolo[4,3-a]quinoxalin-1-one (1) has been found to be an A(2A) versus A(1) selective antagonist (Colotta et al. Arch. Pharm. Pharm. Med. Chem. 1999,332, 39-41). In this paper some novel triazoloquinoxalin-1-ones 4-25 bearing different substituents on the 2-phenyl and/or 4-amino moiety of the parent 4-amino-1,2-dihydro-2-phenyl-1,2,4-triazolo[4,3-a]quinoxalin-1-one (3) have been synthesized and tested in radioligand binding assays at bovine A(1) and A(2A) and cloned human A(3) adenosine receptors (AR). Moreover, the binding activities at the above-mentioned AR subtypes of the 1,4-dione parent compounds 26-31 and their 5-N-alkyl derivatives 33-37 were also evaluated. The substituent on the 2-phenyl ring exerted a different effect on AR subtypes, while replacement of a hydrogen atom of the 4-amino group with suitable substituents yielded selective A(1) or A(3) antagonists. Replacement of a hydrogen atom of the 4-NH2 with an acyl group, or replacement of the whole 4-NH2 with a 4-oxo moiety, shifted the binding activity toward the A(3) AR. The binding results allowed elucidation of the structural requirements for the binding of these novel tricyclic derivatives at each receptor subtype. In particular, A(1) and A(2A) binding required the presence of a proton donor group at position-4, while for A(3) affinity the presence of a proton acceptor in this same region was of paramount importance
A chemoattractant expressed in human sarcoma cells (tumor-derived chemotactic factor, TDCF) is identical to monocyte chemoattractant protein-1/monocyte chemotactic and activating factor (MCP-1/MCAF).
No full textNegative regulators of the interleukin-1 system: receptor antagonists and a decoy receptor
No full text: The IL-1 system includes 2 agonists, alpha and beta, processing and transport molecules, receptor antagonists, signalling receptor, a decoy receptor and an accessory molecule. Negative pathways of regulation include the antagonists, of which 3 isoforms have been cloned and the type II "decoy" receptor. Molecules that regulate inflammation and immunity coordinatively affect different components of the system. The complexity of the system and the existence of unique pathways of negative regulation, the antagonists and the decoy receptor, emphasize the need for a tight control of the production and action of IL-1
Expression of a heat-inducible gene of the HSP70 family in human myelomonocytic cells: regulation by bacterial products and cytokines.
No full textCancer-related inflammation, the seventh hallmark of cancer: links to genetic instability.
No full textDissociation between induction of ornithine decarboxylase and oxidative burst by phorbol esters in a macrophage cell line
No full text: In order to investigate the correlation between stimulation of superoxide generation and induction of ornithine decarboxylase (ODC) by 12-O-tetradecanoylphorbol-13-acetate (TPA) we have used the macrophage cell line J774.16 and a clone derived from this line that, by contrast with the parental line, is unable to generate superoxides in response to TPA. No difference was observed between the normal and the defective cells, with respect to ODC induction by TPA over a wide range of TPA concentrations (0.2-5.0 micrograms/ml). Similar results were obtained comparing resident and caseinate-elicited mouse peritoneal macrophages. Although resident macrophages did not generate superoxides in response to TPA, they did not differ from superoxide-generating, caseinate-elicited macrophages with respect to ODC induction. These data suggest a dissociation between the stimulation of the oxidative burst by TPA and a growth factor-like effect such as ODC induction
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