SYNTHESIS AND PHARMACOLOGICAL EVALUATION OF ENANTIOMERICALLY PURE 4-DEOXY-4-FLUOROMUSCARINES

被引:38
作者
BRAVO, P
RESNATI, G
ANGELI, P
FRIGERIO, M
VIANI, F
ARNONE, A
MARUCCI, G
CANTALAMESSA, F
机构
[1] CNR,CTR STUDIO SOSTANZE ORGAN NAT,I-20133 MILAN,ITALY
[2] DIPARTIMENTO SCI CHIM,I-62032 CAMERINO,ITALY
[3] INST FARMACOL & FARMACOGNOSIA,I-62032 CAMERINO,ITALY
关键词
D O I
10.1021/jm00095a003
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Four isomers of [(4-fluoro-5-methyl-tetrahydrofuran-2-yl)methyl]trimethylammonium iodide (4-deoxy-4-fluoro-muscarines) were prepared in enantiomerically and diastereomerically pure form from (S)-(-)-methyl 4-methylphenyl sulfoxide, ethyl fluoroacetate, and allyl bromide. Their absolute configurations were assigned by H-1 NMR analyses. The four optically pure compounds were tested in vitro on guinea pig and their muscarinic potency was evaluated at M3 (ileum and bladder) and M2 (heart) muscarinic receptor subtypes. Compound 1a, the most potent isomer of the series, was also tested in vivo on pithed rat and its muscarinic activity at the M1 receptor subtype was compared with that of muscarine. Moreover, affinity and relative efficacy were calculated in vitro for this compound at M2 (heart force and rate) and M3 (ileum and bladder) receptors in order to investigate muscarinic receptor heterogeneity. The 4-deoxy-4-fluoromuscarines display a similar trend of potency as the corresponding muscarines and compound 1a shows differences in the affinity constants among the studied tissues. Replacement of a hydroxyl group for a fluorine atom in the 4 position of muscarine produces 1 order of magnitude increase in affinity for cardiac M2 muscarinic receptors controlling rate, while the affinity at cardiac M2 muscarinic receptors controlling force is unchanged, opening the possibility of a further classification of cardiac muscarinic receptors.
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页码:3102 / 3110
页数:9
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