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.
Title: Synthesis of pyridinium analogues of acetylcholine and their interactions with intestinal muscarinic receptors Kuhnen-Clausen D, Hagedorn I, Bill R Ref: Journal of Medicinal Chemistry, 22:177, 1979 : PubMed
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.
Title: Regulatory properties and cooperativity of membrane bound muscarinic receptors of intestinal smooth muscle cells Kuhnen-Clausen D Ref: Croatica Chemica Acta, 47:465, 1975 : PubMed
Title: A novel approach to the questions of allosteric properties or a 'receptor reserve' of drug binding sites of intestinal smooth muscle cells Kuhnen-Clausen D Ref: FEBS Letters, 39:61, 1974 : PubMed
Title: Structure-activity relationship of mono- and bisquaternary pyridines in regard to their parasympatholytic effects Kuhnen-Clausen D Ref: Toxicol Appl Pharmacol, 23:443, 1972 : PubMed
Title: Investigations on the parasympatholytic effect of toxogonin on the guinea-pig isolated ileum Kuhnen-Clausen D Ref: European Journal of Pharmacology, 9:85, 1970 : PubMed
