Portal de Periódicos da CAPES

Synthesis and Pharmacological Characterization of Enantiomerically Pure Muscarinic Agonists: Difluoromuscarines

1997; American Chemical Society; Volume: 40; Issue: 7 Linguagem: Inglês

10.1021/jm960742w

1520-4804

Piero Angeli, Franco Cantalamessa, Roberto Cavagna, Paola Conti, Marco De Amici, Carlo De Micheli, Anna Gamba, Gabriella Marucci,

Fluorine in Organic Chemistry

The four homochiral 4-deoxy-4,4-difluoromuscarine stereoisomers (difluoromuscarines) were prepared in very high enantiomeric excess. A convenient sequence based on the use of natural as well as "unnatural" ethyl lactate allowed the synthesis of target compounds, whose absolute configuration is dictated by that of the starting synthon. Quaternary ammonium salts (+)-5, (−)-5, (−)-6, and (+)-6 were tested in vitro on guinea pig tissues, and their muscarinic potency was evaluated at M2 (heart) and M3 (ileum and bladder) muscarinic receptor subtypes. The eutomer (+)-5 and distomer (−)-5 were also tested in vivo on pithed rat, and their muscarinic activity at the M1 receptor subtype was compared with those of racemic muscarine [(±)-1] and (2S,4R,5S)-4-deoxy-4-fluoromuscarine [(+)-4]. Further pharmacological parameters such as affinity, relative efficacy, and enantioselectivity have been determined for compounds (+)-5 and (−)-5 at M2 (heart force and rate) and M3 (ileum and bladder) receptors in order to investigate muscarinic receptor heterogeneity. The four homochiral difluoromuscarines behave as muscarinic agonists in all the tests with a potency trend which is different from that previously observed with the 4-deoxy-4-fluoromuscarines and (±)-1, thus indicating the intervention of the second fluorine atom on the receptor−ligand interaction. Moreover, the second fluorine atom produces significant differences in the affinity and relative efficacy values of compounds (+)-5 and (−)-5 at M2 and M3 subtypes, which could be attributed to a heterogeneity between the muscarinic receptors mediating heart rate and heart force and those involved in the contraction of ileum and bladder.