Synthesis and muscarinic activity of the chiral forms of methylenemuscarones

• Published in: Farmaco (Società chimica italiana : 1989) Vol. 48; no. 10; p. 1349
• Main Authors: De Amici, M, De Micheli, C, Gianferrara, T, Grana, E, Dondi, G, Ladinsky, H, Schiavi, G
• Format: Journal Article
• Language: English
• Published: France 01-10-1993
• Subjects: Animals; Cerebral Cortex - drug effects; Guinea Pigs; Heart Atria - drug effects; Ileum; Male; Muscarine - analogs & derivatives; Muscarine - chemical synthesis; Muscarine - pharmacology; Muscle Contraction - drug effects; Muscle, Smooth - drug effects; Muscle, Smooth, Vascular - drug effects; Myocardial Contraction - drug effects; Parasympathomimetics - chemical synthesis; Parasympathomimetics - pharmacology; Rats; Rats, Wistar; Receptors, Muscarinic - drug effects; Stereoisomerism; Submandibular Gland - drug effects
• ISSN: 0014-827X

The synthesis of the two pairs of enantiomers of methylenemuscarones 3 and 4 has been accomplished by using (R)- and (S)-lactic esters as starting materials. Due to the existence of different muscarinic receptor subtypes, the compounds were examined for their ability to bind membranes from cerebral cortex (M1), heart (M2), and salivary glands (M3) and were assayed in "in vitro" functional tests as well. The results of such an investigation put in evidence that, in both binding and functional tests, (-)-3 (2S,5S) and (-)-4 (2R,5S) were the eutomers and shared the stereochemistry of the eutomer of muscarone and allomuscarone respectively. It is worth noting that the distomer of 3 and 4 behaves as a partial agonist in the cardiac tissue and as a full agonist in the other preparations. This peculiarity of the chiral forms of 3 and 4 could account for the remarkable selectivity for the ileum observed in the corresponding racemates.