-transparent.png){kind=logo}
The bisbenzylether of the bispyridinium oxime, DUO 3-O (4,4'-Bis-[(2,6-dichlorobenzyloxyimino)-methyl]-1,1'-propane-1,3- diyl-bispyridinium dibromide), has been found to stabilize the antagonist binding to the M2-cholinoceptors which is indicative of an allosteric action. The oxygen of the oxime group was replaced with a nitrogen and a CH2-group leading to DUO 3-N and 3-C, respectively. The allosteric potency of the compounds was characterized by the concentrations which retarded the rate of dissociation of [3H]N-methyl-scopolamine from porcine cardiac cholinoceptors by a factor of 2 (EC50). The hydrazone derivative DUO 3-N was found to be the most active compound (ED50 = 2.7 microM) exceeding in activity DUO 3-O by a factor of 1.6 and DUO 3-C by a factor of 5. No correlation was found between the lipophilicity, determined as octanol/water partition coefficient, and the allosteric potency. The distribution of charges in the molecules was calculated by means of PEOE and displayed as Kohonen maps: The calculations exhibit a shift of the positive charge in the pyridinium ring from the nitrogen to the carbon atom in para-position when going from DUO 3-C to 3-O and 3-N. This shift parallels the rank order of the allosteric potency. From these results the conclusion has been drawn that the between distance the terminal ring-system and the positive charge is pivotal for the interaction of the allosteric modulators with the receptor protein.
J Gasteiger, and
U Holzgrabe, and
E Kostenis, and
K Mohr, and
U Sürig, and
M Wagener
January 1997,
Life sciences,
J Gasteiger, and
U Holzgrabe, and
E Kostenis, and
K Mohr, and
U Sürig, and
M Wagener
May 1994,
Journal of medicinal chemistry,
J Gasteiger, and
U Holzgrabe, and
E Kostenis, and
K Mohr, and
U Sürig, and
M Wagener
April 2006,
Archiv der Pharmazie,
J Gasteiger, and
U Holzgrabe, and
E Kostenis, and
K Mohr, and
U Sürig, and
M Wagener
April 2003,
Neurochemical research,
J Gasteiger, and
U Holzgrabe, and
E Kostenis, and
K Mohr, and
U Sürig, and
M Wagener
October 1996,
European journal of pharmacology,
J Gasteiger, and
U Holzgrabe, and
E Kostenis, and
K Mohr, and
U Sürig, and
M Wagener
January 2003,
Receptors & channels,
J Gasteiger, and
U Holzgrabe, and
E Kostenis, and
K Mohr, and
U Sürig, and
M Wagener
January 1998,
Clinical and experimental pharmacology & physiology,
J Gasteiger, and
U Holzgrabe, and
E Kostenis, and
K Mohr, and
U Sürig, and
M Wagener
March 2010,
Acta pharmacologica Sinica,
J Gasteiger, and
U Holzgrabe, and
E Kostenis, and
K Mohr, and
U Sürig, and
M Wagener
April 1997,
Molecular pharmacology,
J Gasteiger, and
U Holzgrabe, and
E Kostenis, and
K Mohr, and
U Sürig, and
M Wagener
May 1994,
American journal of veterinary research,
