Synthesis and pharmacological investigation of the enantiomers of muscarone and allomuscarone.
A strategy based on the use of (R)- and (S)-lactic ester as starting materials allowed the synthesis of the two enantiomers of muscarone [(-)-1 and (+)-1] and allomuscarone [(-)-5 and (+)-5] in greater than 98% enantiomeric excess. The compounds were examined for their ability to bind to membranes from cerebral cortex (M1), heart (M2), and salivary glands (M3) and to recognize affinity agonist states of the muscarinic receptors. The two pairs of enantiomers were also tested in five functional assays, and their muscarinic potency was determined. In both binding and functional tests, (-)-1 (2S,5S) and (-)-5 (2R,5S) were the eutomers of muscarone and allomuscarone, respectively. The eudismic ratio of muscarone, evaluated in the functional tests, spanned a range of 280-440. These values are substantially different from ones (2.4-10.1) reported in the literature. From a stereochemical point of view, muscarone behaves as muscarine and all other major muscarinic agonists; as a consequence, the hypotheses advanced to account for the anomalies of muscarone no longer have reason to exist.
De Amici
M
M
Istituto Chimico-Farmaceutico dell'Università, Milano, Italy.
Dallanoce
C
C
De Micheli
C
C
Grana
E
E
Barbieri
A
A
Ladinsky
H
H
Schiavi
G
G
Zonta
F
F
D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism; D009116:Muscarine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D009206:Myocardium / Q000378:metabolism; D010277:Parasympathomimetics / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000378:metabolism; D012469:Salivary Glands / Q000378:metabolism; D013237:Stereoisomerism
D010277:Parasympathomimetics; D011976:Receptors, Muscarinic; C002394:muscarone; D009116:Muscarine