| 1931. |
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| 1932. |
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| 1933. |
- Nordvall, Gunnar, et al.
(författare)
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Preparation of piperazinyl quinazolines as 5-HT6 modulators.
- 2007
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Patent (populärvet., debatt m.m.)abstract
- Title compds. represented by the formula I [wherein Q = (hetero)arylalkyl, (hetero)cycloalkylalkyl or alkyl; B = CH or N; R1 = H, OH, halo, alkyl, etc.; R2 = H, (halo)alkyl, aminocarbonylalkyl, etc.; R3 = H, (halo)alkyl or alkylaryl; R4 = CN, halo, alkoxy, etc.; m = 0-2; n = 0-4; and pharmaceutically acceptable salts, solvates or solvated salts thereof] were prepd. as 5-HT6 modulators. For example, reaction of 2,4-dichloroquinazoline with benzenesulfonamide and followed by reaction with N-methylpiperazine, gave N-[2-(4-methylpiperazin-1-yl)quinazolin-4-yl]benzenesulfonamide in 6% yield. The radioligand binding assay showed II having Ki of 1.4 nM. Thus, I and their pharmaceutical compns. are useful for the treatment of 5-HT6 mediated disorders, such as Alzheimer's disease, schizophrenia, obesity or Parkinson's disease. [on SciFinder(R)]
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| 1934. |
- Nordvall, Gunnar, et al.
(författare)
-
Preparation of piperazinyl quinazolines as 5-HT6 modulators.
- 2007
-
Patent (populärvet., debatt m.m.)abstract
- Title compds. represented by the formula I [wherein Q = (hetero)arylalkyl; R1 = OH, halo, alkyl, etc.; R2, R3 = independently H, (halo)alkyl, aminocarbonylalkyl, etc.; n = 0-3; and pharmaceutically acceptable salts, solvates or solvated salts thereof] were prepd. as 5-HT6 modulators. For example, reaction of 2-chloro-4-(4-methylpiperazin-1-yl)quinazoline with N-methyl-4-chlorobenzenesulfonamide gave II in 10% yield. The radioligand binding assay showed II having Ki of 200 nM. Thus, I and their pharmaceutical compns. are useful for the treatment of 5-HT6 mediated disorders, such as Alzheimer's disease, schizophrenia, obesity or Parkinson's disease. [on SciFinder(R)]
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| 1935. |
- Norlund, Lena, et al.
(författare)
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A novel thrombomodulin gene mutation in a patient suffering from sagittal sinus thrombosis
- 1997
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Ingår i: Thrombosis and Haemostasis. - 0340-6245. ; 78:4, s. 1164-1166
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Tidskriftsartikel (refereegranskat)abstract
- Thrombomodulin is an endothelial cell membrane glycoprotein that promotes protein C activation. It has been clearly demonstrated that the anticoagulant functions of the protein C system are important in the prevention of thromboembolic disease. Patients with protein C or protein S deficiency and/or resistance to activated protein C (APC resistance) are at higher risk for developing thromboembolic disease. The first mutation in the thrombomodulin gene was discovered in an American patient suffering from pulmonary embolism at the age of 45 (Ohlin and Marlar 1995). Here we report a case of sagittal sinus thrombosis in a 42-year-old Swedish woman. She was found to carry a heterozygous point mutation changing G127 to A, predicting an Ala25 to a Thr change in the mature thrombomodulin protein. This mutation was also found in her 16-year-old daughter, who so far has not suffered from any thrombotic events. The patient had no other detectable prothrombotic genetic defects associated with the coagulation system. This case supports the hypothesis of an association between mutations in the thrombomodulin gene and venous thrombosis.
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| 1936. |
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| 1937. |
- Norman, Caitlyn, et al.
(författare)
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Detection in seized samples, analytical characterization, and in vitro metabolism of the newly emerged 5-bromo-indazole-3-carboxamide synthetic cannabinoid receptor agonists
- 2023
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Ingår i: Drug Testing and Analysis. - : WILEY. - 1942-7603 .- 1942-7611.
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Tidskriftsartikel (refereegranskat)abstract
- Synthetic cannabinoid receptor agonists (SCRAs) are a diverse class of new psychoactive substances (NPS) and new structural scaffolds have emerged on the recreational drug market since the enactment of Chinese SCRA analog controls in 2021. This study reports the first SCRAs to be detected with a bromide at the 5 position (5 ' Br) on the phenyl ring of the indazole core and without a tail moiety. ADB-5 ' Br-INACA (ADMB-5 ' Br-INACA) and MDMB-5 ' Br-INACA were detected in seized samples from Scottish prisons, Belgian customs, and US forensic casework. The brominated analog with a tail moiety, ADB-5 ' Br-BUTINACA (ADMB-5 ' Br-BUTINACA), was also detected in Scottish prisons and US forensic casework. The metabolites of these compounds and the predicted compound MDMB-5 ' Br-BUTINACA were identified through incubation with primary human hepatocytes to aid in their toxicological identification. The bromide on the indazole remains intact on metabolites, allowing these compounds to be easily distinguished in toxicological samples from their non-brominated analogs. Glucuronidation was more common for tail-less analogs than their butyl tail-containing counterparts. Forensic toxicologists are advised to update their analytical methods with the characteristic ions for these compounds, as well as their anticipated urinary markers: amide hydrolysis and monoOH at tert-butyl metabolites (after beta-glucuronidase treatment) for ADB-5 ' Br-INACA; monoOH at tert-butyl and amide hydrolysis metabolites for ADB-5 ' Br-BUTINACA; and ester hydrolysis metabolites with additional metabolites for MDMB-5 ' Br-INACA and MDMB-5 ' Br-BUTINACA. Toxicologists should remain vigilant to the emergence of new SCRAs with halogenation of the indazole core and tail-less analogs, which have already started to emerge. This study reports the detection of the new synthetic cannabinoids ADB-5 ' Br-INACA and MDMB-5 ' Br-INACA in Scotland, Belgium, and the US, and ADB-5 ' Br-BUTINACA in Scotland and the US. These compounds, along with the predicted compound MDMB-5 ' Br-BUTINACA, were incubated with primary human hepatocytes to examine metabolic pathways and aid in toxicological identification.image
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| 1938. |
- Norström, Eva, et al.
(författare)
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Effects of factor Xa and protein S on the individual activated protein C-mediated cleavages of coagulation factor Va.
- 2006
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Ingår i: Journal of Biological Chemistry. - 1083-351X. ; 281:42, s. 31486-31494
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Tidskriftsartikel (refereegranskat)abstract
- Activated protein C inhibits the procoagulant function of activated factor V (FVa) through proteolytic cleavages at Arg-306, Arg-506, and Arg-679. The cleavage at Arg-506 is kinetically favored but protected by factor Xa (FXa). Protein S has been suggested to annihilate the inhibitory effect of FXa, a proposal that has been challenged. To elucidate the effects of FXa and protein S on the individual cleavage sites of FVa, we used recombinant FVa:Q306/Q679 and FVa: Q506/Q679 variants, which can only be cleaved at Arg-506 and Arg-306, respectively. In the presence of active site blocked FXa (FXa-1.5-dansyl-GluGly-Arg), the FVa inactivation was followed over time, and apparent second order rate constants were calculated. Consistent with results on record, we observed that FXa-1.5-dansylGlu-Gly- Arg decreased the Arg-506 cleavage by 20-fold, with a half-maximum inhibition of similar to 2 nM. Interestingly and in contrast to the inhibitory effect of FXa on the 506 cleavage, FXa stimulated the Arg-306 cleavage. Protein S counteracted the inhibition by FXa of the Arg-506 cleavage, whereas protein S and FXa yielded additive stimulatory effect of the cleavage at Arg-306. This suggests that FXa and protein S interact with distinct sites on FVa, which is consistent with the observed lack of inhibitory effect on FXa binding to FVa by protein S. We propose that the apparent annihilation of the FXa protection of the Arg-506 cleavage by protein S is due to an enhanced rate of Arg-506 cleavage of FVa not bound to FXa, resulting in depletion of free FVa and dissociation of FXa-FVa complexes.
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| 1939. |
- Norström, Eva
(författare)
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The regulation of factor Va activity by activated protein C -Importance of the individual activated protein C cleavage sites in factor Va
- 2003
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The subject of this thesis is the activated protein C (APC)-mediated inactivation of factor Va. The activated form of factor V (FVa) is a procoagulant cofactor for Factor Xa (FXa) in the conversion of prothrombin to thrombin. The procoagulant function of FVa is down regulated by APC through proteolytic cleavage at three sites, Arg306, Arg506 and Arg679. The cleavage at Arg506 is kinetically favored, while the cleavage at Arg306 is needed for full loss of procoagulant activity. The cleavage at Arg679 is believed to play a minor role for the loss of FVa activity. Numerous plasma components have been reported to influence the inactivation of FVa. Factor V variants were constructed recombinantly to evaluate the importance of each of the three APC cleavage sites in the FVa inactivation and how they are influenced by numerous plasma components. The stimulation of FVa inactivation by protein S, originally believed to only involve the Arg306 cleavage, was in this thesis shown to affect all three cleavage sites. The inhibition by FXa was confirmed to selectively involve the Arg506 cleavage and protein S was shown to counteract the inhibition, due to competitive binding of protein S and FXa to FVa. The prothrombin inhibition was shown to involve all three cleavage sites. Three natural occurring mutations in the FV gene were expressed and characterized. In FV Hong Kong and FV Cambridge the amino acid at the 306 site is substituted. Unlike the more common mutation that affects the Arg506 site (FV Leiden), these mutations were shown not to cause a serious APC-resistance phenotype and the FVa inactivation was not seriously impaired. In addition to its procoagulant function, intact FV has an anticoagulant function, as it works as a cofactor for APC in the degradation of Factor VIIIa. The APC cofactor activity is severely impaired in FV Leiden, but our studies show that in FV Hong Kong and FV Cambridge this activity is only partly hampered. FV Liverpool is a mutation found in two brothers with thrombotic tendency. The mutation causes the position of an additional carbohydrate in FV. We showed that the FVa inactivation and FV cofactor function were impaired due to impaired binding of APC and protein S to FVa.
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| 1940. |
- Nurmikko, P., et al.
(författare)
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Production and characterization of novel anti-prostate-specific antigen (PSA) monoclonal antibodies that do not detect internally cleaved Lys145-Lys146 inactive PSA
- 2000
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Ingår i: Clinical Chemistry. - : Oxford University Press (OUP). - 0009-9147 .- 1530-8561. ; 46:10, s. 1610-1618
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Tidskriftsartikel (refereegranskat)abstract
- Background: The nature of free, uncomplexed prostate-specific antigen (s) in the circulation is still unknown. In this study, we developed novel anti-PSA antibodies using PSA produced by a metastasized cancer cell line, LNCaP, as an immunogen. Methods: Hybridoma cell lines were screened with different methods that aimed at finding antibodies specific for the forms of free PSA produced by LNCaP cell line. Obtained antibodies were further studied for their characteristics related to previously characterized monoclonal antibodies. Results: Numerous anti-PSA antibodies were obtained, of which four represented unique epitopes previously unrecognized by us. One free-PSA-specific antibody was bound to PSA on two distinct epitopes, and one antibody was bound to the carboxyl-terminal peptide of PSA. Two antibodies were found to bind to the peptide sequence adjacent to the internal cleavage site Lys145-Lys146. These antibodies failed to recognize internally cleaved PSA at Lys145-Lys146. We could not find anti-proPSA antibodies despite the fact that LNCaP PSA contained more than one-half of the zymogen form of PSA. Conclusions: We report, for the first time, novel anti-PSA antibodies that do not recognize internally cleaved PSA at Lys145-Lys146 and thus are specific for intact, unclipped PSA. (C) 2000 American Association for Clinical Chemistry.
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