In search of a dopamine D
2 and serotonin 5-HT
3 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 D
2 and the serotonin 5-HT
3 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 D
2 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 D
2 receptor binding affinity along with a potent 5-HT
3 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 D
2 receptor than that of metoclopramide (IC
50=17.5—61.0 n
M vs. 483 n
M). 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 D
2 and the 5-HT
3 receptors, while the corresponding (
S)-enantiomer had a potent and selective serotonin 5-HT
3 receptor binding affinity.
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