Hagedorn I

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Full name : Hagedorn Ilse

First name : Ilse

Mail : Chemical Laboratory, University of Freiburg, Freiburg

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Country : Germany

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References (15)

Title : HLo 7 dimethanesulfonate, a potent bispyridinium-dioxime against anticholinesterases - Eyer_1992_Arch.Toxicol_66_603
Author(s) : Eyer P , Hagedorn I , Klimmek R , Lippstreu P , Loffler M , Oldiges H , Spohrer U , Steidl I , Szinicz L , Worek F
Ref : Archives of Toxicology , 66 :603 , 1992
Abstract : HL 7 dimethanesulfonate (1-[[[4-(aminocarbonyl)pyridinio]methoxy]methyl]-2,4-bis [(hydroxyimino)methyl]pyridinium dimethanesulfonate) is a broad-spectrum reactivator against highly toxic organophosphorus compounds. The compound was synthesized by a new route with the carcinogenic bis(chloromethyl)ether being substituted by the non-mutagenic bis(methylsulfonoxymethyl)ether. The very soluble dimethanesulfonate of obidoxime was also prepared by this way. HL 7 dimethanesulfonate is the first water-soluble salt of HL 7 that should be suitable for the wet/dry autoinjector technology, because aqueous solutions of HL 7 are not very stable (calculated shelf-life 0.2 years when stored at 8 degrees C, 1 M solution, pH 2.5). The crystalline preparation contains 96% of the syn/syn-isomer, less than 2% of the syn/anti-isomer and some minor identified by-products. HL 7 was very efficient in reactivating acetylcholinesterase (AChE) blocked by organophosphates as long as ageing did not prevent dephosphylation. HL 7 was superior to HI 6 (1-[[[4-(aminocarbonyl)pyridinio]methoxy]methyl]-2- [(hydroxyimino)methyl]pyridinium dichloride) in reactivating soman and sarin-inhibited AChE from erythrocytes, and literature data indicate that HL 7 exceeds HI 6 by far in reactivating tabun-inhibited AChE. In atropine-protected, soman-poisoned mice HL 7 was three times more potent than HI 6 (protective ratio 5 versus 2.5), and in sarin-poisoned mice HL 7 was 10 times more potent than HI 6 (protective ratio 8 for both oximes). In atropine-protected guinea-pigs HL 7 was less effective than HI 6 (protective ratio: 2.3 versus 5.2 for soman; 5.2 versus 6.8 for sarin; 4.3 versus 3.8 for tabun). The mean survival time of anaesthetized guinea-pigs exposed to 5 LD50 soman (6.3 min) was increased by atropine (27 min) and atropine + HL (57 min). HL 7 alone did not prolong the survival. The most impressive effect of HL 7 was on respiration: 3 min after i.v. injection of HL 7 and atropine, the depressed respiration increased rapidly to 60% of control and remained at that level during the observation period (60 min). With atropine alone, respiration recovered only slowly. Behavioural and physiologic parameters were determined in atropine-protected mice exposed to a sublethal soman dose. The running performance was significantly improved by HL 7. Even central symptoms, e.g. hypothermia and convulsions, were decreased markedly by HL 7 (evaluation 60 min after poisoning). The pharmacokinetic data for HL 7 in male beagle dogs are similar to those of HI 6.
ESTHER : Eyer_1992_Arch.Toxicol_66_603
PubMedSearch : Eyer_1992_Arch.Toxicol_66_603
PubMedID: 1482283

Title : The bispyridinium-dioxime HLo-7. A potent reactivator for acetylcholinesterase inhibited by the stereoisomers of tabun and soman - De Jong_1989_Biochem.Pharmacol_38_633
Author(s) : De Jong LP , Verhagen MA , Langenberg JP , Hagedorn I , Loffler M
Ref : Biochemical Pharmacology , 38 :633 , 1989
Abstract : Purification of (+)-tabun was accomplished by treatment with electric eel acetylcholinesterase (AChE) in order to bind contaminating (-)-tabun and with purified (+)-tabun shown similar properties in reactivation reactions with oximes (pH 7.5, 25 degrees). The bispyridinium-2,4-dioxime HL-7 is a substantially active reactivator for these inhibited enzymes as well as for human erythrocyte AChE inhibited with (-)-tabun. In contrast, the corresponding bispyridinium-2-monooxime HI-6 does not show any activity at similar reaction conditions. HL-7 is also much more active than HI-6 when used as a reactivator for electric eel AChE inhibited by some N-unsubstituted derivatives of tabun. Surprisingly, HL-7 is highly active in reactivating human erythrocyte and rat diaphragm AChE inhibited by C(+)P(+/-)-and C(-)P(+/-)-soman, i.e. at least as active as HI-6, which is the most potent reactivator for soman-inhibited AChE reported so far. To our knowledge, HL-7 is the first compound reported in literature that shows a potent reactivating activity towards both tabun-inhibited AChE and soman-inhibited AChE.
ESTHER : De Jong_1989_Biochem.Pharmacol_38_633
PubMedSearch : De Jong_1989_Biochem.Pharmacol_38_633
PubMedID: 2917018

Title : Study on the stability of the oxime HI 6 in aqueous solution - Eyer_1988_Arch.Toxicol_62_224
Author(s) : Eyer P , Hagedorn I , Ladstetter B
Ref : Archives of Toxicology , 62 :224 , 1988
Abstract : HI 6 (Pyridinium, 1-[[[4-(aminocarbonyl)pyridinio]methoxy]methyl]-2-[(hydro xyimino) methyl]-dichloride is an effective antidote against poisoning with extremely toxic organophosphates. Because of conflicting reports on the stability of HI 6 in aqueous solutions, we studied the factors influencing its stability. HI 6 has been shown to be most stable in acidic solution between pH 2 and 3. At that pH, HI 6 decomposes probably by attack of nucleophiles on the methylene carbon atom of the animal-acetal bond of the "ether bridge". HI 6 decomposition follows first order kinetics. From Arrhenius plots of the decay of HI 6 at various concentrations it became obvious that the rate of decomposition increased with increasing HI 6 concentration with simultaneous decrease in the energy of activation. To decide whether the pyridinium compound itself or its anions are responsible for the enhanced decomposition, we studied the influence of chloride, phosphate and iodide. These anions stimulated the decay of HI 6 at increasing strength; their effect, however, was small as compared to that brought about by the pyridinium oxime itself. Since 1-methylisonicotinamide chloride had virtually no effect in contrast to 1-methylpyridinium-2-aldoxime chloride, we conclude that the oximate anion is responsible for the intermolecular attack on HI 6. At present, we recommend storage of HI 6 at concentrations not exceeding 0.1 M in aqueous solution at pH 2.5 and low temperatures. Under these conditions an apparent shelf-life of 20 years is calculated when HI 6 is stored at 8 degrees C.
ESTHER : Eyer_1988_Arch.Toxicol_62_224
PubMedSearch : Eyer_1988_Arch.Toxicol_62_224
PubMedID: 3196158

Title : Stability study of HI-6 dichloride in various anticholinergic formulations -
Author(s) : Brown ND , Gray RR , Stermer-Cox MG , Doctor BP , Hagedorn I
Ref : Journal of Chromatography , 315 :389 , 1984
PubMedID: 6526905

Title : Interactions of bisquaternary pyridine salts (H-oximes) with cholinergic receptors - Kuhnen-Clausen_1983_Arch.Toxicol_54_171
Author(s) : Kuhnen-Clausen D , Hagedorn I , Gross G , Bayer H , Hucho F
Ref : Archives of Toxicology , 54 :171 , 1983
Abstract : Certain recently developed antidotes of the bispyridinium type, commonly called "H-oximes" (HGG 12, 21, 42, 52, 65, 70, 89, and HGG 90) have been investigated as to their effects on muscarinic and nicotinic acetylcholine receptors. These compounds clearly discriminate between these two types of receptors being more potent inhibitors of the muscarinic receptor with inhibitory constants in the micromole range. (The corresponding values for the nicotinic receptor are in the range of 0.1 mM.) However, the inhibitory potency in the binding assay does not correlate with the ED50 values obtained against soman in mice. The site of antidotal action therefore appears not to be the nicotinic acetylcholine receptor. Binding to the muscarinic receptors may partially contribute to the effects against soman in vivo.
ESTHER : Kuhnen-Clausen_1983_Arch.Toxicol_54_171
PubMedSearch : Kuhnen-Clausen_1983_Arch.Toxicol_54_171
PubMedID: 6661028

Title : Synthesis of pyridinium analogues of acetylcholine and their interactions with intestinal muscarinic receptors - Kuhnen-Clausen_1979_J.Med.Chem_22_177
Author(s) : Kuhnen-Clausen D , Hagedorn I , Bill R
Ref : Journal of Medicinal Chemistry , 22 :177 , 1979
Abstract : N-(beta-Acetoxyethyl)pyridinium salts were synthesized and tested for muscarinic receptor interactions by the guinea pig ileum assay. Agonist activity indicates that receptor binding is substantially retained when the ammonium group of acetylcholine is formally replaced by a pyridinium ring. Introduction of alkyl groups into the ring yields antagonists. The 4-tert-butylpyridinium derivative is proved to have an activity superior to that of the 4-methylpyridinium salt. Competitive antagonism is favored by the more hydrophobic property of the tert-butyl group. A nonpolar area is suggested to be situated in the direct vicinity of the anionic binding sites of muscarinic receptors. The interaction of hydrophobic substituents with this area determines the antimuscarinic properties of pyridinium salts.
ESTHER : Kuhnen-Clausen_1979_J.Med.Chem_22_177
PubMedSearch : Kuhnen-Clausen_1979_J.Med.Chem_22_177
PubMedID: 423196

Title : [Reactivation of phosphorylated acetylcholinesterase. Isomeric bisquaternary salts of pyridine aldoximes] - Hagedorn_1978_Arzneimittelforschung_28_2055
Author(s) : Hagedorn I , Stark I , Schoene K , Schenkel H
Ref : Arzneimittelforschung , 28 :2055 , 1978
Abstract : Mono-quaternary salts Z have been prepared from pyridine-aldoximes and 1,3-dihalogen compounds. These were used to synthesize asymmetrical bis-quaternary pyridine-oximes with three-membered bridge. The effect of reactivation of phosphorylated AChE by these substances is less than that of obidoxim (Toxogonin).
ESTHER : Hagedorn_1978_Arzneimittelforschung_28_2055
PubMedSearch : Hagedorn_1978_Arzneimittelforschung_28_2055
PubMedID: 582905

Title : [Betaines of quaternary salts of pyridine-2-and -4-aldoxim (author's transl)] - Hagedorn_1976_Arzneimittelforschung_26_753
Author(s) : Hagedorn I , Gundel WH
Ref : Arzneimittelforschung , 26 :753 , 1976
Abstract : The monobetaine derived from the AChE-ractivator bis-[4-hydroxyiminomethyl-pyridinium-(1)-methyl]-either dichloride (obidoxim; Toxogonin), was shown to be in solution an intramolecular CT-complex. Some betaines of quaternary salts of pyridine-aldoximes were isolated.
ESTHER : Hagedorn_1976_Arzneimittelforschung_26_753
PubMedSearch : Hagedorn_1976_Arzneimittelforschung_26_753
PubMedID: 786301

Title : [Synthesis and Quaternation of Pyridine-aldoxim Alkylethers (author's transl)] - Hagedorn_1976_Arzneimittelforschung_26_1273
Author(s) : Hagedorn I , Gundel WH , Hoose J , Jenter C
Ref : Arzneimittelforschung , 26 :1273 , 1976
Abstract : Using known procedures, alkylethers of pyridine-aldoxime not described as yet were prepared and transformed into pyridinium salts. The application of a solution of a,a'-di-iodo-dimethyl-ether proved especially useful in the synthesis of bisquarternary salts with formaldehyde-acetal bridge. All the new substances are ineffective in a paraoxon poisoning. On the other hand, some salts show protective action in soman intoxication.
ESTHER : Hagedorn_1976_Arzneimittelforschung_26_1273
PubMedSearch : Hagedorn_1976_Arzneimittelforschung_26_1273
PubMedID: 1036912

Title : [Reactivation of phosphorylated acetylcholinesterase (AChE): quaternary salts of vinylogous pyridinaldoxims (author's transl)]. [German] - Hagedorn_1976_Arzneimittelforschung_26_1515
Author(s) : Hagedorn I , Hohler W
Ref : Arzneimittelforschung , 26 :1515 , 1976
Abstract : Application of Wittig reaction to 4-pyridinecarboxaldehyde leads to 4-beta-formylvinylpyridine (62%). The corresponding oxime (4-(2)) can be quaternized with alpha,alpha'-bis-(chloromegonin), and with methyliodide one to 4-PAM (4-(3)). In this case the formal insertion of an ethylenic double bond between the pyridinium ring and the aldoxime group decreases the ability to reactivate phosphorylated acetylcholinesterase (AChE).
ESTHER : Hagedorn_1976_Arzneimittelforschung_26_1515
PubMedSearch : Hagedorn_1976_Arzneimittelforschung_26_1515
PubMedID: 1036947

Title : Reactivation of phosphorylated acetylcholinesterase--dependence upon activator acidity -
Author(s) : Hagedorn I , Stark I , Lorenz HP
Ref : Angew Chem Int Ed Engl , 11 :307 , 1972
PubMedID: 4626426

Title : [Reactivation of phosphorylated acetylcholine esterase with oximes: contribution to the study of the reaction course] -
Author(s) : Hagedorn I , Gundel WH , Schoene K
Ref : Arzneimittelforschung , 19 :603 , 1969
PubMedID: 5819160

Title : [Quatenary hydroxyiminomethylpyridinium salts. The dischloride of Bis-(4-hydroxyiminomethyl-1-pyridinium-methyl)-ether (LuEH6), a new reactivator of acetylcholinesterase inhibited by organic phosphoric acid esters] -
Author(s) : Luttringhaus A , Hagedorn I
Ref : Arzneimittelforschung , 14 :1 , 1964
PubMedID:

Title : [Structural explanation of xanthocillin\; a new antibiotic] -
Author(s) : Hagedorn I , Tonjes H
Ref : Pharmazie , 12 :567 , 1957
PubMedID: 13494165

Title : [Structure of xanthocillin, a new antibiotic] -
Author(s) : Hagedorn I , Tonjes H
Ref : Pharmazie , 11 :409 , 1956
PubMedID: 13370319