5-HT3 RECEPTOR ANTAGONISTS .2. 4-HYDROXY-3-QUINOLINECARBOXYLIC ACID-DERIVATIVES

被引:48
作者
HAYASHI, H [1 ]
MIWA, Y [1 ]
ICHIKAWA, S [1 ]
YODA, N [1 ]
MIKI, I [1 ]
ISHII, A [1 ]
KONO, M [1 ]
YASUZAWA, T [1 ]
SUZUKI, F [1 ]
机构
[1] KYOWA HAKKO KOGYO CO LTD,PHARMACEUT RES LABS,1188 SHIMOTOGARI,NAGAIZUMI,SHIZUOKA 411,JAPAN
关键词
D O I
10.1021/jm00057a011
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
A series of 4-hydroxy-3-quinolinecarboxylic acid derivatives (6) and 4-hydroxy-2-oxo-1,2-dihydro-3-quinolinecarboxylic acid derivatives (7) were designed and synthesized as 5-HT3 receptor antagonists. Molecular modeling studies suggested that the 3-carbonyl moiety in 6 was almost coplanar to the plane of an aromaticring, but in 7 there was a 30-degrees deviation. 4-Hydroxy substitution in quinoline derivatives enhanced affinity for the 5-HT3 receptors, and endo-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-4-hydroxy-3-quinolinecarboxamide (6f) exhibited the most potent activity in the Bezold-Jarisch (B-J) reflex test (ED50=0.1 mug/kg, iv) among quinoline derivatives 6. Although 4-hydroxy-2-oxo-1,2-dihydro-3-quinolinecarboxamide derivatives (7a) exhibited higher affinity (e.g., 7d: K(i) = 0.48 nM) for the 5-HT3 receptors than ondansetron (K(i) = 7.6 nM) or granisetron (K(i) = 2.1 nM), these amides showed less potent activity in the B-J reflex test than the reference compounds. Interestingly, the ester derivatives 7c, 7f, and 7h eliminated affinity for the 5-HT3 receptors. These unusual structure-activity relationships and the deviation of the 3-carbonyl moiety from the plane of an aromatic ring suggest that the active conformation of 7a might be different from the proposed one for the preceding 5-HT3 antagonists. Thus, 6f was chosen for further studies. No receptor binding for a variety of ligands was significantly antagonized by 6f. Comparing the ratios of the ED50 value in the B-J reflex test (rat, iv) with the LD50 value in acute lethal toxicity (mouse, iv), 6f was proved to have a 600-fold wider margin of safety than ondansetron. Compound 6f dose-dependently attenuated both the incidence and frequency of emetic episodes induced by cisplatin in the dog (ED50 = 14 mug/kg, iv) more potently than ondansetron (ED50 = 210 mug/kg, iv). Compound 6f (KF-20170) is now under further investigation as a drug for treating gastrointestinal disorder.
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页码:617 / 626
页数:10
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共 52 条
[31]  
LEIBUNDGUT U, 1987, LANCET, V1, P1198
[32]   CHARACTERIZATION OF [H-3] QUIPAZINE BINDING TO 5-HYDROXYTRYPTAMINE3 RECEPTORS IN RAT-BRAIN MEMBRANES [J].
MILBURN, CM ;
PEROUTKA, SJ .
JOURNAL OF NEUROCHEMISTRY, 1989, 52 (06) :1787-1792
[33]   VALIDATION OF THE GENERAL-PURPOSE QUANTA(R)3.2/CHARMM(R) FORCE-FIELD [J].
MOMANY, FA ;
RONE, R .
JOURNAL OF COMPUTATIONAL CHEMISTRY, 1992, 13 (07) :888-900
[34]  
MYLECHARANE EJ, 1987, 1987 P IUPHAR C SAT
[35]  
NEIJT HC, 1988, N-S ARCH PHARMACOL, V337, P493
[36]   VAGAL SENSORY RECEPTORS AND THEIR REFLEX EFFECTS [J].
PAINTAL, AS .
PHYSIOLOGICAL REVIEWS, 1973, 53 (01) :159-227
[37]   5-HYDROXYTRYPTAMINE RECEPTOR SUBTYPES - MOLECULAR, BIOCHEMICAL AND PHYSIOLOGICAL CHARACTERIZATION [J].
PEROUTKA, SJ .
TRENDS IN NEUROSCIENCES, 1988, 11 (11) :496-500
[38]   THE PHARMACOLOGY AND FUNCTION OF 5-HT3 RECEPTORS [J].
RICHARDSON, BP ;
ENGEL, G .
TRENDS IN NEUROSCIENCES, 1986, 9 (09) :424-428
[39]   IDENTIFICATION OF SEROTONIN M-RECEPTOR SUBTYPES AND THEIR SPECIFIC BLOCKADE BY A NEW CLASS OF DRUGS [J].
RICHARDSON, BP ;
ENGEL, G ;
DONATSCH, P ;
STADLER, PA .
NATURE, 1985, 316 (6024) :126-131
[40]   THE SYNTHESIS OF SOME 4-QUINOLINOLS AND 4-CHLOROQUINOLINES BY THE ETHOXYMETHYLENEMALONIC ESTER METHOD [J].
RIEGEL, B ;
LAPPIN, GR ;
ADELSON, BH ;
JACKSON, RI ;
ALBISETTI, CJ ;
DODSON, RM ;
BAKER, RH .
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1946, 68 (07) :1264-1266