The Experts below are selected from a list of 1428 Experts worldwide ranked by ideXlab platform
Richard B. Silverman - One of the best experts on this subject based on the ideXlab platform.
-
design synthesis and biological testing of potential heme coordinating nitric oxide synthase inhibitors
Bioorganic & Medicinal Chemistry, 2006Co-Authors: Elizabeth A Litzinger, Pavel Martásek, Linda J Roman, Richard B. SilvermanAbstract:Based on computer modeling of the active site of nitric oxide synthases (NOS), a series of 10 amidine compounds (9-18) was designed including potential inhibitors that involve the coordination of side-chain functional groups with the iron of the heme cofactor. The most potent and selective compound was the methylthio amidine analogue 9, which was more potent than L-Nitroarginine with 185-fold selectivity for inhibition of neuronal NOS over endothelial NOS. It also exhibited time-dependent inhibition, but did not involve the mechanism previously proposed for other amidine inhibitors of NOS. None of the compounds, however, exhibited heme-binding characteristics according to absorption spectroscopy.
-
structures of the neuronal and endothelial nitric oxide synthase heme domain with d Nitroarginine containing dipeptide inhibitors bound
Biochemistry, 2004Co-Authors: Mack Flinspach, Richard B. Silverman, Hui Huang, Joumana Jamal, Weiping Yang, Thomas L PoulosAbstract:In a continuing effort to unravel the structural basis for isoform-selective inhibition of nitric oxide synthase (NOS) by various inhibitors, we have determined the crystal structures of the nNOS and eNOS heme domain bound with two D-Nitroarginine-containing dipeptide inhibitors, D-Lys-D-Arg N O 2-NH 2 and D-Phe-D-Arg N O 2-NH 2 . These two dipeptide inhibitors exhibit similar binding modes in the two constitutive NOS isozymes, which is consistent with the similar binding affinities for the two isoforms as determined by K i measurements. The D-Nitroarginine-containing dipeptide inhibitors are not distinguished by the amino acid difference between nNOS and eNOS (Asp 597 and Asn 368, respectively) which is key in controlling isoform selection for nNOS over eNOS observed for the L-Nitroarginine-containing dipeptide inhibitors reported previously [Flinspach, M., et al. (2004) Nat. Struct. Mol. Biol. 11, 54-59]. The lack of a free α-amino group on the D-Nitroarginine moiety makes the dipeptide inhibitor steer away from the amino acid binding pocket near the active site. This allows the inhibitor to extend into the solvent-accessible channel farther away from the active site, which enables the inhibitors to explore new isoform-specific enzyme-inhibitor interactions. This might be the structural basis for why these D-Nitroarginine-containing inhibitors are selective for nNOS (or eNOS) over iNOS.
-
nω Nitroarginine containing dipeptide amides potent and highly selective inhibitors of neuronal nitric oxide synthase
Journal of Medicinal Chemistry, 1999Co-Authors: Hui Huang, Pavel Martásek, Linda J Roman, Bettie Sue Siler Masters, Richard B. SilvermanAbstract:Selective inhibition of the isoforms of nitric oxide synthase (NOS) could be therapeutically useful in the treatment of certain disease states arising from the overproduction of nitric oxide (NO). Recently, we reported the dipeptide methyl ester, d-Phe-d-ArgNO2-OMe (19), as a modest inhibitor of nNOS (Ki = 2 μM), but with selectivity over iNOS as high as 1800-fold (Silverman, R. B.; Huang, H.; Marletta, M. A.; Martasek, P. J. Med. Chem. 1997, 40, 2813−2817). Here a library of 152 dipeptide amides containing Nitroarginine and amino acids other than Phe are synthesized and screened for activity. Excellent inhibitory potency and selectivity for nNOS over eNOS and iNOS is achieved with the dipeptide amides containing a basic amine side chain (20−24), which indicates a possible electrostatic (or hydrogen bonding) interaction at the enzyme active site. The most potent nNOS inhibitor among these compounds is l-ArgNO2-l-Dbu-NH2 (23) (Ki = 130 nM), which also exhibits the highest selectivity over eNOS (>1500-fold)...
-
Selective Inhibition of Neuronal Nitric Oxide Synthase by Nω-Nitroarginine- and Phenylalanine-Containing Dipeptides and Dipeptide Esters
Journal of medicinal chemistry, 1997Co-Authors: Richard B. Silverman, Hui Huang, Michael A. Marletta, Pavel MartásekAbstract:A series of Nω-Nitroarginine (ArgNO2)- and phenylalanine-containing dipeptides and dipeptide esters were synthesized as potential selective inhibitors of neuronal nitric oxide synthase (nNOS). All of the dipeptides and dipeptide esters are competitive inhibitors of nNOS, macrophage nitric oxide synthase (iNOS), and endothelial nitric oxide synthase (eNOS), except for the ones that contain d-ArgNO2 (8−10, 12, 13), which are uncompetitive inhibitors of iNOS but competitive inhibitors of nNOS and eNOS. None of the dipeptides or dipeptide esters tested (1, 2, 12, 13) exhibited time-dependent inhibition of any of the NOS isoforms, unlike Nω-nitro-l-arginine itself, which does, although it is reversible. The order of the amino acids in the dipeptide or dipeptide ester is important to selectivity, and the selectivity depends on the chirality of the amino acids. In the case of the corresponding benzyl esters (5 vs 6), both dipeptides favor iNOS over nNOS and eNOS inhibition. All of the dipeptide methyl esters con...
Pavel Martásek - One of the best experts on this subject based on the ideXlab platform.
-
design synthesis and biological testing of potential heme coordinating nitric oxide synthase inhibitors
Bioorganic & Medicinal Chemistry, 2006Co-Authors: Elizabeth A Litzinger, Pavel Martásek, Linda J Roman, Richard B. SilvermanAbstract:Based on computer modeling of the active site of nitric oxide synthases (NOS), a series of 10 amidine compounds (9-18) was designed including potential inhibitors that involve the coordination of side-chain functional groups with the iron of the heme cofactor. The most potent and selective compound was the methylthio amidine analogue 9, which was more potent than L-Nitroarginine with 185-fold selectivity for inhibition of neuronal NOS over endothelial NOS. It also exhibited time-dependent inhibition, but did not involve the mechanism previously proposed for other amidine inhibitors of NOS. None of the compounds, however, exhibited heme-binding characteristics according to absorption spectroscopy.
-
nω Nitroarginine containing dipeptide amides potent and highly selective inhibitors of neuronal nitric oxide synthase
Journal of Medicinal Chemistry, 1999Co-Authors: Hui Huang, Pavel Martásek, Linda J Roman, Bettie Sue Siler Masters, Richard B. SilvermanAbstract:Selective inhibition of the isoforms of nitric oxide synthase (NOS) could be therapeutically useful in the treatment of certain disease states arising from the overproduction of nitric oxide (NO). Recently, we reported the dipeptide methyl ester, d-Phe-d-ArgNO2-OMe (19), as a modest inhibitor of nNOS (Ki = 2 μM), but with selectivity over iNOS as high as 1800-fold (Silverman, R. B.; Huang, H.; Marletta, M. A.; Martasek, P. J. Med. Chem. 1997, 40, 2813−2817). Here a library of 152 dipeptide amides containing Nitroarginine and amino acids other than Phe are synthesized and screened for activity. Excellent inhibitory potency and selectivity for nNOS over eNOS and iNOS is achieved with the dipeptide amides containing a basic amine side chain (20−24), which indicates a possible electrostatic (or hydrogen bonding) interaction at the enzyme active site. The most potent nNOS inhibitor among these compounds is l-ArgNO2-l-Dbu-NH2 (23) (Ki = 130 nM), which also exhibits the highest selectivity over eNOS (>1500-fold)...
-
Selective Inhibition of Neuronal Nitric Oxide Synthase by Nω-Nitroarginine- and Phenylalanine-Containing Dipeptides and Dipeptide Esters
Journal of medicinal chemistry, 1997Co-Authors: Richard B. Silverman, Hui Huang, Michael A. Marletta, Pavel MartásekAbstract:A series of Nω-Nitroarginine (ArgNO2)- and phenylalanine-containing dipeptides and dipeptide esters were synthesized as potential selective inhibitors of neuronal nitric oxide synthase (nNOS). All of the dipeptides and dipeptide esters are competitive inhibitors of nNOS, macrophage nitric oxide synthase (iNOS), and endothelial nitric oxide synthase (eNOS), except for the ones that contain d-ArgNO2 (8−10, 12, 13), which are uncompetitive inhibitors of iNOS but competitive inhibitors of nNOS and eNOS. None of the dipeptides or dipeptide esters tested (1, 2, 12, 13) exhibited time-dependent inhibition of any of the NOS isoforms, unlike Nω-nitro-l-arginine itself, which does, although it is reversible. The order of the amino acids in the dipeptide or dipeptide ester is important to selectivity, and the selectivity depends on the chirality of the amino acids. In the case of the corresponding benzyl esters (5 vs 6), both dipeptides favor iNOS over nNOS and eNOS inhibition. All of the dipeptide methyl esters con...
Hui Huang - One of the best experts on this subject based on the ideXlab platform.
-
structures of the neuronal and endothelial nitric oxide synthase heme domain with d Nitroarginine containing dipeptide inhibitors bound
Biochemistry, 2004Co-Authors: Mack Flinspach, Richard B. Silverman, Hui Huang, Joumana Jamal, Weiping Yang, Thomas L PoulosAbstract:In a continuing effort to unravel the structural basis for isoform-selective inhibition of nitric oxide synthase (NOS) by various inhibitors, we have determined the crystal structures of the nNOS and eNOS heme domain bound with two D-Nitroarginine-containing dipeptide inhibitors, D-Lys-D-Arg N O 2-NH 2 and D-Phe-D-Arg N O 2-NH 2 . These two dipeptide inhibitors exhibit similar binding modes in the two constitutive NOS isozymes, which is consistent with the similar binding affinities for the two isoforms as determined by K i measurements. The D-Nitroarginine-containing dipeptide inhibitors are not distinguished by the amino acid difference between nNOS and eNOS (Asp 597 and Asn 368, respectively) which is key in controlling isoform selection for nNOS over eNOS observed for the L-Nitroarginine-containing dipeptide inhibitors reported previously [Flinspach, M., et al. (2004) Nat. Struct. Mol. Biol. 11, 54-59]. The lack of a free α-amino group on the D-Nitroarginine moiety makes the dipeptide inhibitor steer away from the amino acid binding pocket near the active site. This allows the inhibitor to extend into the solvent-accessible channel farther away from the active site, which enables the inhibitors to explore new isoform-specific enzyme-inhibitor interactions. This might be the structural basis for why these D-Nitroarginine-containing inhibitors are selective for nNOS (or eNOS) over iNOS.
-
nω Nitroarginine containing dipeptide amides potent and highly selective inhibitors of neuronal nitric oxide synthase
Journal of Medicinal Chemistry, 1999Co-Authors: Hui Huang, Pavel Martásek, Linda J Roman, Bettie Sue Siler Masters, Richard B. SilvermanAbstract:Selective inhibition of the isoforms of nitric oxide synthase (NOS) could be therapeutically useful in the treatment of certain disease states arising from the overproduction of nitric oxide (NO). Recently, we reported the dipeptide methyl ester, d-Phe-d-ArgNO2-OMe (19), as a modest inhibitor of nNOS (Ki = 2 μM), but with selectivity over iNOS as high as 1800-fold (Silverman, R. B.; Huang, H.; Marletta, M. A.; Martasek, P. J. Med. Chem. 1997, 40, 2813−2817). Here a library of 152 dipeptide amides containing Nitroarginine and amino acids other than Phe are synthesized and screened for activity. Excellent inhibitory potency and selectivity for nNOS over eNOS and iNOS is achieved with the dipeptide amides containing a basic amine side chain (20−24), which indicates a possible electrostatic (or hydrogen bonding) interaction at the enzyme active site. The most potent nNOS inhibitor among these compounds is l-ArgNO2-l-Dbu-NH2 (23) (Ki = 130 nM), which also exhibits the highest selectivity over eNOS (>1500-fold)...
-
Selective Inhibition of Neuronal Nitric Oxide Synthase by Nω-Nitroarginine- and Phenylalanine-Containing Dipeptides and Dipeptide Esters
Journal of medicinal chemistry, 1997Co-Authors: Richard B. Silverman, Hui Huang, Michael A. Marletta, Pavel MartásekAbstract:A series of Nω-Nitroarginine (ArgNO2)- and phenylalanine-containing dipeptides and dipeptide esters were synthesized as potential selective inhibitors of neuronal nitric oxide synthase (nNOS). All of the dipeptides and dipeptide esters are competitive inhibitors of nNOS, macrophage nitric oxide synthase (iNOS), and endothelial nitric oxide synthase (eNOS), except for the ones that contain d-ArgNO2 (8−10, 12, 13), which are uncompetitive inhibitors of iNOS but competitive inhibitors of nNOS and eNOS. None of the dipeptides or dipeptide esters tested (1, 2, 12, 13) exhibited time-dependent inhibition of any of the NOS isoforms, unlike Nω-nitro-l-arginine itself, which does, although it is reversible. The order of the amino acids in the dipeptide or dipeptide ester is important to selectivity, and the selectivity depends on the chirality of the amino acids. In the case of the corresponding benzyl esters (5 vs 6), both dipeptides favor iNOS over nNOS and eNOS inhibition. All of the dipeptide methyl esters con...
Thomas L Poulos - One of the best experts on this subject based on the ideXlab platform.
-
structures of the neuronal and endothelial nitric oxide synthase heme domain with d Nitroarginine containing dipeptide inhibitors bound
Biochemistry, 2004Co-Authors: Mack Flinspach, Richard B. Silverman, Hui Huang, Joumana Jamal, Weiping Yang, Thomas L PoulosAbstract:In a continuing effort to unravel the structural basis for isoform-selective inhibition of nitric oxide synthase (NOS) by various inhibitors, we have determined the crystal structures of the nNOS and eNOS heme domain bound with two D-Nitroarginine-containing dipeptide inhibitors, D-Lys-D-Arg N O 2-NH 2 and D-Phe-D-Arg N O 2-NH 2 . These two dipeptide inhibitors exhibit similar binding modes in the two constitutive NOS isozymes, which is consistent with the similar binding affinities for the two isoforms as determined by K i measurements. The D-Nitroarginine-containing dipeptide inhibitors are not distinguished by the amino acid difference between nNOS and eNOS (Asp 597 and Asn 368, respectively) which is key in controlling isoform selection for nNOS over eNOS observed for the L-Nitroarginine-containing dipeptide inhibitors reported previously [Flinspach, M., et al. (2004) Nat. Struct. Mol. Biol. 11, 54-59]. The lack of a free α-amino group on the D-Nitroarginine moiety makes the dipeptide inhibitor steer away from the amino acid binding pocket near the active site. This allows the inhibitor to extend into the solvent-accessible channel farther away from the active site, which enables the inhibitors to explore new isoform-specific enzyme-inhibitor interactions. This might be the structural basis for why these D-Nitroarginine-containing inhibitors are selective for nNOS (or eNOS) over iNOS.
Fernando Q Cunha - One of the best experts on this subject based on the ideXlab platform.
-
tumor necrosis factor α and interleukin 1β mediate the production of nitric oxide involved in the pathogenesis of ifosfamide induced hemorrhagic cystitis in mice
The Journal of Urology, 2002Co-Authors: R A Ribeiro, Helano C Freitas, M C Campos, C C Santos, F C Figueiredo, Gerly Anne De Castro Brito, Fernando Q CunhaAbstract:Purpose: We investigated the participation of nitric oxide in ifosfamide induced hemorrhagic cystitis in mice, and the involvement of tumor necrosis factor (TNF)-α and interleukin (IL)-1β in the induction of nitric oxide production in this model.Materials and Methods: Hemorrhagic cystitis was induced in mice by 100 to 400 mg./kg. ifosfamide and evaluated 6, 12, 24 or 48 hours thereafter by certain parameters, including vesical edema measurements, microscopic analysis and immunohistochemical testing for inducible nitric oxide synthase. Ifosfamide injected mice were pretreated with 10 to 40 mg./kg. of the nitric oxide synthesis inhibitor L-NG-Nitroarginine methyl ester, 80 mg./kg. of mesna, a chemical antagonist of acrolein and the urotoxic metabolite of ifosfamide, 50 μl. antiserum against TNF-α and IL-1β per mouse, 45 mg./kg. of the selective TNF-α synthesis inhibitor thalidomide or 200 mg./kg. of the TNF-α and IL-1β synthesis inhibitor pentoxifylline.Results: Ifosfamide induced vesical edema, which peake...
-
involvement of nitric oxide in the pathogenesis of cyclophosphamide induced hemorrhagic cystitis
American Journal of Pathology, 1997Co-Authors: M V Souzafiho, Fernando Q Cunha, M V Lima, M M Pompeu, G Ballejo, Ribeiro Rde AAbstract:The involvement of nitric oxide (NO) and the potential modulation of NO synthase (NOS) activity by platelet-activating factor were investigated in a rat model of cyclophosphamide-induced hemorrhagic cystitis. Male Wistar rats received a single intraperitoneal injection of cyclophosphamide, and cystitis was evaluated 6, 12, 24, 48, and 72 hours later by determining the changes in bladder wet weight and plasma protein extravasation and the macro- and microscopic morphological alterations. In addition, NOS activity and NADPH-diaphorase histochemistry were studied in bladder tissues. Normal bladders showed extensive NADPH-diaphorase staining and a high level of constitutive NOS whereas the activity of inducible NOS was almost undetectable. Cyclophosphamide dose- and time-dependently increased the bladder wet weight and bladder plasma protein extravasation. These events were accompanied at a microscopic level by urothelial necrosis, sloughing, ulceration, hemorrhage, and leukocyte infiltration. Cyclophosphamide also increased the levels of inducible NOS but reduced those of constitutive NOS. The NOS inhibitors L-NG-Nitroarginine methyl ester and L-NG-Nitroarginine significantly reduced the cyclophosphamide-induced plasma protein extravasation and urothelial damage. This reduction was completely reversed by L-arginine but not by D-arginine. The administration of the platelet-activating factor antagonist BN 52021 decreased the cyclophosphamide-induced plasma protein extravasation as well as the rise in inducible NOS activity but had no effect on the fall in constitutive NOS activity. These results suggest that endogenous NO participates in the urothelial damage and in the inflammatory events leading to cyclophosphamide-induced hemorrhagic cystitis. Platelet-activating factor also seems to be involved in the pathogenesis of this condition, possibly by inducing NOS.