Data di Pubblicazione:
1992
Citazione:
SYNTHESIS AND PHARMACOLOGICAL INVESTIGATION OF STEREOISOMERIC MUSCARINES / M. De Amici, C. Dallanoce, C. De Micheli, E. Grana, G. Dondi, H. Ladinsky, G.B. Schiavi, F. Zonta. - In: CHIRALITY. - ISSN 0899-0042. - 4:4(1992), pp. 230-239.
Abstract:
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 (-)-l as well as the other six isomers. The eudismic
ratios (E.R.) deduced from the two functional tests were 324 and 331.
Tipologia IRIS:
01 - Articolo su periodico
Keywords:
TOTAL SYNTHESIS; CHIRAL MUSCARINES; IODOCYCLIZATION PROCESS; MUSCARINIC
RECEPTOR SUBTYPE-M1, SUBTYPE-M2, AND SUBTYPE-M3; AFFINITY STATES;
EUDISMIC RATIO
Elenco autori:
M. De Amici, C. Dallanoce, C. De Micheli, E. Grana, G. Dondi, H. Ladinsky, G.B. Schiavi, F. Zonta
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