Synthesis and characterization of all four isomers of the muscarinic agonist 2'-methylspiro[1-azabicyclo[2.2.2]octane-3,4'-[1,3]dioxolane].
The four separated isomers of the muscarinic agonist 1, previously known as AF30, have been synthesized by a route that has allowed the absolute stereochemistry of each isomer to be assigned. With the chirality of (-)-camphanic acid known, X-ray analysis of the more crystalline intermediate diastereomeric camphanate 5A allowed the absolute stereochemistry at the quinuclidine chiral center to be determined. Each diastereomer was separately transformed into the spirodioxolane with concomitant introduction of the second chiral center. Chromatographic separation followed by a second crystal structure determination revealed the absolute stereochemistry of all four isomers of 1. Detailed biological evaluation of each isomer indicated that while the 3(R),2'(S) isomer was the most active in binding studies, it was the 3(R),2'(R) isomer that displayed the largest functional selectivity between ganglion (M-1 site) and heart (M-2 site). With the same internal chiral standard, the absolute configuration of the more active enantiomer of 3 was shown to be S, confirming earlier literature reports.
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001643:Bridged Bicyclo Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D001952:Bridged-Ring Compounds / Q000138:chemical synthesis*; D004148:Dioxolanes / Q000138:chemical synthesis* / Q000494:pharmacology; D004149:Dioxoles / Q000138:chemical synthesis*; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D008968:Molecular Conformation; D010277:Parasympathomimetics / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011976:Receptors, Muscarinic / Q000187:drug effects*; D013141:Spiro Compounds; D013237:Stereoisomerism; D014961:X-Ray Diffraction
D001643:Bridged Bicyclo Compounds; D001952:Bridged-Ring Compounds; D004148:Dioxolanes; D004149:Dioxoles; D010277:Parasympathomimetics; D011976:Receptors, Muscarinic; D013141:Spiro Compounds; C052394:2'-methylspiro-(1-azabicyclo(2.2.2.)octane-3,4'-(1,3)-dioxolane)