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Direct thrombin inhibitors built on the azaphenylalanine scaffold provoke degranulation of mast cellsPeternel, Luka ...The main structural feature of direct thrombin inhibitor LK-732 responsible for the appropriate interaction at the thrombin active site is a strong basic group.A possibility that a strong basic group ... of LK-732 might contribute to the mast cell degranulation effect and consequent reduction of tracheal air flow (TAF) and fall of mean arterial blood pressure (MAP) in rats was investigated in the present study. At doses up to 5 mgžkg (i.v.), LK-732 did not cause significant changes of TAF and MAP. At 7 mgžkg (i.v.), a sudden reduction of TAF and a fall of MAP was observed within 5 min after LK-732 administration (75% mortality, p=0.007).A less basic direct thrombin inhibitorLK-658 (21 mgž kg, i.v.) did not significantly disturb TAF and MAP.A reduction of TAF and a fall of MAP caused by LK-732 (7 mgžkg,i.v.) was a lomost completely abolished in rats with degranulated mast cells (0% mortality, p=0.008). LK-732 concentration-dependently degranulated rat peritoneal mast cells in vitro (pEC 50=1.92 0.05 M).A structure-activity relationship (SAR) study revealed that the terminal basic groups attached to the aromatic ring are responsible for the mast cell degranulation effect. A good correlation was observed between mast cell degranulation and pKb of analogues of LK-732 (R2 =0.49), but not between mast cell degranulation and thrombin K i (R2 =0.23). LK-732-induced reduction ofTAF, the fall of MAP and high mortality originate from LK- 732-induced mast cell degranulation. As judged by the SAR study, this effect could be overcome by reducing the basicity of LK-732Source: Thrombosis and haemostasis. - ISSN 0340-6245 (vol. 95, no. 2, 2006, str. 294-300)Type of material - article, component partPublish date - 2006Language - englishCOBISS.SI-ID - 1881457
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Database name | Field | Year |
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Links to authors' personal bibliographies | Links to information on researchers in the SICRIS system |
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Peternel, Luka | 24465 |
Štempelj, Mateja | 21386 |
Černe, Manica | 05088 |
Zega, Anamarija | 18633 |
Obreza, Aleš | 19061 |
Oblak, Marko, 1976- | 20159 |
Drevenšek, Gorazd | 13310 |
Budihna, Metka, 1937- | 02740 |
Stanovnik, Lovro | 01547 |
Urleb, Uroš | 01878 |
Source: Personal bibliographies
and: SICRIS
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