Synthesis and pharmacological characterization of enantiomerically pure muscarinic agonists: Difluoromuscarines
Articolo
Data di Pubblicazione:
1997
Citazione:
Synthesis and pharmacological characterization of enantiomerically pure
muscarinic agonists: Difluoromuscarines / P. Angeli, F. Cantalamessa, R. Cavagna, P. Conti, M. De Amici, C. De Micheli, A. Gamba, G. Marucci. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 40:7(1997), pp. 1099-1103.
Abstract:
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 M(2) (heart) and M(3) (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 M(1)
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
M(2) (heart force and rate) and M(3) (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 M(2) and M(3) 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.}
Tipologia IRIS:
01 - Articolo su periodico
Elenco autori:
P. Angeli, F. Cantalamessa, R. Cavagna, P. Conti, M. De Amici, C. De Micheli, A. Gamba, G. Marucci
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