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-HT_3 and Dopamine D_2 Receptors Dual Antagonist

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概要

• 論文の詳細を見る

• 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-I,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 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 D_2 and the 5-HT_3 receptors, while the corresponding (S)-enantiomer had a potent and selective serotonin 5-HT3 receptor binding affinity.

• 社団法人日本薬学会の論文
• 2002-07-01

著者

• Kato S

  Medicinal Chemistry Group Chemistry Research Laboratories Dainippon Pharmaceutical Co. Ltd.

• HIROKAWA Yoshimi

  Medicinal Chemistry Group, Chemistry Research Laboratories, Dainippon Pharmaceutical Co. Ltd.

• HARADA Hiroshi

  Medicinal Chemistry Group, Chemistry Research Laboratories, Dainippon Pharmaceutical Co. Ltd.

• YOSHIKAWA Takashi

  Discovery Pharmacology II Group, Pharmacolgy & Microbiology Research Laboratories, Dainippon Pharmac

• YOSHIDA Naoyuki

  Discovery Pharmacology II Group, Pharmacolgy & Microbiology Research Laboratories, Dainippon Pharmac

• KATO Shiro

  Medicinal Chemistry Group, Chemistry Research Laboratories, Dainippon Pharmaceutical Co. Ltd.

• Kato S

  Tokushima Bunri Univ. Jpn

• Kato Shiro

  Medicinal Chemistry Group Chemistry Research Laboratories Dainippon Pharmaceutical Co. Ltd.

• Yoshida N

  School Of Pharmaceutical Sciences Toho University

• Yoshida Naoyuki

  Discovery Pharmacology Ii Group Pharmacolgy & Microbiology Research Laboratories Dainippon Pharm

• Harada H

  Department Of Kidney Transplant Surgery Sapporo City General Hospital

• Hirokawa Y

  Medicinal Chemistry Group Chemistry Research Laboratories Dainippon Pharmaceutical Co. Ltd.

• Yoshikawa Takashi

  Discovery Pharmacology Ii Group Pharmacolgy & Microbiology Research Laboratories Dainippon Pharm

• Harada Hiroshi

  Department Of Urology Hokkaido University School Of Medicine

関連論文

• Development of Potent Serotonin-3(5-HT_3) Receptor Antagonists. II. Structure-Activity Relationships of N-(1-Benzyl-4-methylhexahydro-1H-1,4-diazepin-6-yl)carboxamides
• Development of Potent Serotonin-3 (5-HT_3) Receptor Antagonists. I. Structure-Activity Relationships of 2-Alkoxy-4-amino-5-chlorobenzamide Derivatives
• Discovery of a Novel and Potent Human and Rat β_3-Adrenergic Receptor Agonist, [3-[(2R)-[[(2R)-(3-Chlorophenyl)-2-hydroxyethyl]amino]propyl]-1H-indol-7-yloxy]acetic Acid
• 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-HT_3 and Dopamine D_2 Receptors Dual Antagonist
• An Efficient Synthesis of 6-Substituted Aminohexahydro-1H-1,4-diazepines from 2-Substituted Aminopropenals
• ^Tc-DTPA dynamic SPECT and CT volumetry for measuring split renal function in live kidney donors
• Efficient Synthesis of (R)-6-Benzyloxycarbonylamino-1-methyl-4-(3-methylbenzyl)hexahydro-1,4-diazepine. I
• Synthesis and Biological Activity of 4-Amino-5-chloro-2-ethoxy-3-hydroxybenzamides, Metabolites of a New Gastroprokinetic Agent, Mosapride
• A Practical Preparation of Methyl 2-Methoxy-6-metholaminopyridine-3-carboxylate from 2, 6-Dichloro-3-trifluoromethylpyridine
• An Efficient Synthesis of 5-Bromo-2-methoxy-6-methylaminopyridine-3-carboxylic Acid
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• Asynchronous (heterochronic) bilateral renal infarction associated with primary antiphospholipid syndrome
• Pre-emptive renal transplantation in children
• Renal arteriovenous malformation with thrombus in the inferior vena cava
• Effect of Mosapride Citrate Hydrate on the Colon Cleansing Action of Polyethylene Glycol Electrolyte Lavage Solution (PEG-ELS) in Guinea Pigs
• Kidney-Alone Transplantation in Diabetic Patients with End-Stage Renal Disease
• Limited Sampling Strategy for Estimating Area under the Concentration Curve for Mycophenolic Acid in Renal Transplant Recipients with Co-administration of Tacrolimus
• Affinity of Mosapride Citrate, a New Gastroprokinetic Agent,for 5-HT4 Receptors in Guinea Pig Ileum
• Idiopathic and Spontaneously Regressing Thrombus in Right Renal Vein and Inferior Vena Cava
• Squamous metaplasia mimicking papillary carcinoma in the upper urinary tract
• Successful Kidney Transplantation Ameliorates Arterial Stiffness in End-Stage Renal Disease Patients

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