Synthesis and pharmacological investigation of new chiral muscarinic antagonists.
The two pairs of enantiomers of isoxazolidin-3-ones 3 and 4 were synthesized by means of Lipase PS-catalyzed hydrolyses of suitable racemic butyrates. The same butyrates were also employed as key intermediates in the preparation of racemic 3 and 4. The antimuscarinic potency of the new compounds was assayed in two in vitro functional tests. The eutomers (-)-3 and (-)-4 share the same stereochemistry (5R) of the most potent enantiomer of "azamuscarone" 2, a structurally related muscarinic agonist. Such a spatial arrangement around the chiral center of 2-4, coupled with the low values of eudismic ratio, represents an anomaly among the chiral muscarinic ligands. This anomaly was accounted for by the absence of a chiral center at C-2, a position whose configuration is crucial in determining the high enantioselectivity of muscarinic agonists and antagonists.
Carnielli
M
M
Dipartimento di Scienze Farmaceutiche dell'Università, Trieste, Italy.
De Amici
M
M
De Micheli
C
C
Gianferrara
T
T
Maurich
V
V
Zacchigna
M
M
Grana
E
E
Boselli
C
C
D000818:Animals; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D018727:Muscarinic Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D018727:Muscarinic Antagonists