- Synthesis and structure-activity relationships of 4-amino-5-chloro-N-(1,4- dialkylhexahydro-1,4-diazepin-6-yl)-2-methoxybenzamide derivatives, novel and potent serotonin 5-HT3 and dopamine D2 receptors dual antagonist
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In search of a dopamine D2 and serotonin 5-HT3 receptors dual antagonist as a potential broad antiemetic agent, a number of benzamides were prepared from 4-amino-5-chloro-2-methoxybenzoic acid derivatives and 6-amino-1,4-dialkylhexahydro-1,4-diazepines and evaluated for their binding affinity for the dopamine D2 and the serotonin 5-HT3 receptors using rat brain synaptic and rat cortical membranes, respectively. From the results of both in vitro receptor binding and in vivo biological assays for the dopamine D2 receptor, 1-ethyl-4-methylhexahydro-1,4- diazepine ring was selected as an optimum amine moiety. Introduction of one methyl group on the nitrogen atom at the 4-position and/or modification of the substituent at the 5-position of the 4-amino-5-chloro-2-methoxybenzoyl moiety caused a marked increase in the dopamine D2 receptor binding affinity along with a potent 5-HT3 receptor binding affinity. Among the compounds, 5-chloro-N-(1-ethyl-4-methylhexahydro-1,4-diazepin-6-yl)-2-methoxy-4- methylaminobenzamide (82), 5-bromo (110), and 5-iodo (112) analogues exhibited a much higher affinity for the dopamine D2 receptor than that of metoclopramide (IC50=17.5-61.0 nM vs. 483 nM). In particular, 82 showed a potent antagonistic activity for both receptors in vivo tests. Optical resolution of the racemate 82 brought about a dramatic change in the pharmacological profile with the (R)-enantiomer exhibiting a strong affinity for both the dopamine D2 and the 5-HT3 receptors, while the corresponding (S)-enantiomer had a potent and selective serotonin 5-HT 3 receptor binding affinity.
- Hirokawa, Yoshimi,Harada, Hiroshi,Yoshikawa, Takashi,Yoshida, Naoyuki,Kato, Shiro
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p. 941 - 959
(2007/10/03)
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- A novel series of N-(hexahydro-1,4-diazepin-6-yl) and N-(hexahydroazepin-3-yl)benzamides with high affinity for 5-HT3 and dopamine D2 receptors
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A novel series of benzamides with a hexahydro-1,4-diazepine or hexahydroazepine ring in the amine moiety were prepared, and their binding affinities for 5-HT3 and dopamine 4 receptors were evaluated. The R isomer of the 1-ethyl-4-methylhexahydro-1,4-diazepinylbenzamide (R)-22 had potent affinity for both receptors. The R-enantiomer of the corresponding 1-ethylhexahydroazepinylbenzamide 28 showed potent affinity for dopamine D2 receptors with reduced affinity for 5-HT3 receptors, while the S isomer was found to be a potent and selective 5-HT3 receptor antagonist.
- Hirokawa, Yoshimi,Morie, Toshiya,Yamazaki, Hiroshi,Yoshida, Naoyuki,Kato, Shiro
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p. 619 - 624
(2007/10/03)
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- Novel N-(alkyl)-N-(2-haloethyl)-aminomethylphosphonic acids, a method for the preparation thereof and their use in the preparation of starch ether derivatives
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Starch ether derivatives are prepared by reacting a starch base with N-(2-haloethyl)iminobis(methylene)diphosphonic acid or with a N-(alkyl)-N-(2-haloethyl)aminomethylphosphonic acid. The derivatives contain aminophosphonic acid groups (or their salts) as
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