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.

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.

SYNTHESIS AND PHARMACOLOGICAL INVESTIGATION OF STEREOISOMERIC MUSCARINES

M. De Amici
Primo
;
C. Dallanoce
Secondo
;
C. De Micheli;
1992

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.
TOTAL SYNTHESIS; CHIRAL MUSCARINES; IODOCYCLIZATION PROCESS; MUSCARINIC RECEPTOR SUBTYPE-M1, SUBTYPE-M2, AND SUBTYPE-M3; AFFINITY STATES; EUDISMIC RATIO
Settore CHIM/08 - Chimica Farmaceutica
Article (author)
File in questo prodotto:
Non ci sono file associati a questo prodotto.
Pubblicazioni consigliate

Caricamento pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/184412
Citazioni
  • ???jsp.display-item.citation.pmc??? 0
  • Scopus 16
  • ???jsp.display-item.citation.isi??? 21
social impact