title: Synthesis and pharmacological investigation of new chiral muscarinic antagonists.
abstract: 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.
authors.affiliation: Dipartimento di Scienze Farmaceutiche dell'Università, Trieste, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Carnielli
authors.forename: M
authors.initials: M
authors.lastname: De Amici
authors.forename: C
authors.initials: C
authors.lastname: De Micheli
authors.forename: T
authors.initials: T
authors.lastname: Gianferrara
authors.forename: V
authors.initials: V
authors.lastname: Maurich
authors.forename: M
authors.initials: M
authors.lastname: Zacchigna
authors.forename: E
authors.initials: E
authors.lastname: Grana
authors.forename: C
authors.initials: C
authors.lastname: Boselli
mesh_terms: 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
chemical_list: D018727:Muscarinic Antagonists