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.
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-HT3 receptor binding affinity.
Medicinal Chemistry Group, Chemistry Research Laboratories, Dainippon Pharmaceutical Co. Ltd, Suita, Osaka, Japan. Yoshimi-hirokawa@dainippon-pharm.co.jp
Yoshimi
Y
Hirokawa
Hiroshi
H
Harada
Takashi
T
Yoshikawa
Naoyuki
N
Yoshida
Shiro
S
Kato
D000818:Animals; D000932:Antiemetics / Q000138:chemical synthesis* / Q000494:pharmacology*; D001058:Apomorphine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D001549:Benzamides / Q000138:chemical synthesis* / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D018492:Dopamine Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology*; D065127:Dopamine D2 Receptor Antagonists; D004639:Emetics / Q000037:antagonists & inhibitors / Q000494:pharmacology; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D051381:Rats; D011985:Receptors, Serotonin / Q000187:drug effects*; D044406:Receptors, Serotonin, 5-HT3; D012702:Serotonin Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D000932:Antiemetics; D001549:Benzamides; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D004639:Emetics; D007202:Indicators and Reagents; D011985:Receptors, Serotonin; D044406:Receptors, Serotonin, 5-HT3; D012702:Serotonin Antagonists; D001058:Apomorphine