Amidines (guanidine, formamidine, and acetamidine) were introduced as substitutes for the cationic heads present in atropine, scopolamine, and corresponding quaternary derivatives. Amidine systems are intermediate in structure between tertiary amines and quaternary compounds, at least as regards ionization and electronic properties, but differ from the latter in shape (planar not tetrahedral). They have additional binding opportunities on account of their hydrogen-bond-forming capacity. The effect of the introduction of these cationic heads on the affinity for different muscarinic acetyl choline receptor (m-AcChR) subtypes was investigated in vitro, in binding displacement studies, and in functional tests on isolated organs. All new compounds (3a,b-5a,b) showed high affinity for the m-AcChR considered, comparable or slightly inferior to that of the parent drugs (1a-e). The new amidine derivatives proved effective as spasmolytic agents, with little tendency to cause central effects. However, no separation was achieved of spasmolytic and other untoward effects, like inhibition of salivation. Thus, amidine moieties are effective bioisosteric substitutes for conventional cationic heads present in antimuscarinic agents. Their unusual physical-chemical properties make them useful tools when modulation of pharmacokinetic or pharmacodynamic effects is required.
The synthesis of the eight stereoisomers of muscarine has been efficiently accomplished by utilizing the two enantiomers of lactic esters as starting material. The synthetic strategy is based on a SnCl4-catalyzed addition of allyltrimethylsilane to O-protected lactic aldehydes followed by an iodocyclization process. All the final derivatives possess an enantiomeric excess higher than 98%. The four pairs of enantiomers bound to M1, M2, and M3 muscarinic receptor subtypes in membranes from cerebral cortex, heart, and salivary glands, respectively, and recognized heterogeneous states of the receptors. Of the eight isomers, only natural muscarine (+)-1 recognized three affinity states of the M2 receptor. The compound was also the only one to show selectivity in the binding study, demonstrating 37- to 44-fold higher affinity for the M2 than for the M1 or M3 receptors. In addition, the compounds were tested in functional assays on isolated guinea pig atria (M2 receptors) and ileum (mixed population of M2 and M3 receptors) and their muscarinic potencies were determined. Among the eight isomers, again only (+)-1 enantiomer was found to be very active on both tissues. Its potency was more than two orders of magnitude higher than that of its enantiomer (-)-1 as well as the other six isomers. The eudismic ratios (E.R.) deduced from the two functional tests were 324 and 331.
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