Variation of the oxime function of bispyridinium-type allosteric modulators of M2-cholinoceptors.
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.
Gasteiger
J
J
Computer-Chemie-Centrum, Universität Erlangen.
Holzgrabe
U
U
Kostenis
E
E
Mohr
K
K
Sürig
U
U
Wagener
M
M
D000494:Allosteric Regulation; D000818:Animals; D001285:Atropine; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D008958:Models, Molecular; D009206:Myocardium / Q000378:metabolism; D010091:Oximes / Q000737:chemistry*; D011726:Pyridinium Compounds / Q000737:chemistry*; D011869:Radioligand Assay; D011976:Receptors, Muscarinic / Q000737:chemistry* / Q000378:metabolism; D013500:Surface Tension; D013552:Swine
D010091:Oximes; D011726:Pyridinium Compounds; D011976:Receptors, Muscarinic; D001285:Atropine