Modifications in Ach structure (Modification of the Ethylene Bridge …
Modifications in Ach structure
carbamic acid ester of choline (carbachol),
overcome problem of chemical instability of acetylcholine due to its rapid hydrolysis.
Choline esters of
As would be predicted by Ing's rule of five, when the acetyl group is replaced by higher homologs (i.e. propionyl or butyryl groups)
the resulting esters are less potent than acetylcholine
Modification of the Ethylene Bridge
Replacement of the hydrogen atoms of the ethylene bridge by alkyl groups larger than methyl
affords compounds much less active than acetylcholine
A methyl group on the
to the quaternary nitrogen affords acetyl- α-methylcholine
than muscarinic potency; this compound is
not used as a therapeutic agent
methyl group on the
to the quaternary nitrogen affords acetyl-ß-methylcholine
The addition of methyl groups to either one or both of the ethylene carbons results in asymmetric molecules exhibiting optical isomerism.
The muscarinic receptors and acetylcholinesterase (AChE) display stereoselectivity for the enantiomers of acetyl-ß-methylcholine
The S(+) enantiomer is equipotent with acetylcholine, and the R(-) enantiomer is about 20-fold less potent
This stability to AChE hydrolysis as well as the AChE inhibitory effect of the R(-) enantiomer may explain why methacholine (racemic acetyl-ß-methylcholine) produces a longer duration of action than acetylcholine.
Acetylcholinesterase hydrolyzes the S(+) isomer much slower (about half the rate) than acetylcholine. The R(-) isomer is not hydrolyzed by AChE but is a weak competitive inhibitor of the enzyme.
which has muscarinic potency almost equivalent to that of acetylcholine; it has selectivity for muscarinic receptors.
Ing´s rule of five
which is suggests that there should be no more than five atoms between the nitrogen and the terminal hydrogen atom for maximal muscarinic potency.
larger molecules may bind to the receptor, they lack efficacy and demonstrate antagonist properties.
Alkyl substituents on the nitrogen ( R1,R2,R3)
successive replacement of the methyl groups with hydrogen atoms to afford a tertiary, secondary, or primary amine
successively diminishing muscarinic activity.
Replacement of only one methyl group by an ethyl or propyl group
is active but much less so than acetylcholine
When the methyl groups are replaced by
methyl groups on the nitrogen were r
eplaced by larger alkyl
replaced by arsenic, sulfur, or selenium
less active and
not used clinically.
only compounds possessing a positive charge on a nitrogen atom are active