Structural manipulation on the catecholic fragment of dopamine D(1) receptor agonist 1-phenyl-N-methyl-benzazepines

A series of new benzazepines with modification on the catecholic fragment were designed. The 8-hydroxyl group, other than the 7-hydroxyl was confirmed crucial to the interaction with the dopamine D1 receptor. Subsequent replacement of the 7-hydroxyl with benzylamino groups was found tolerable. 7-(m-...

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Bibliographic Details
Published in:European journal of medicinal chemistry 2014-10, Vol.85, p.16-26
Main Authors: Zhang, Jing, Huang, Jiye, Song, Zilan, Guo, Lin, Cai, Wenxian, Wang, Yun, Zhen, Xuechu, Zhang, Ao
Format: Article
Language:English
Subjects:
Animals
Benzazepines - agonists
Benzazepines - chemistry
Benzazepines - metabolism
Catechols - chemistry
CHO Cells
Cricetinae
Cricetulus
HEK293 Cells
Humans
Rats
Receptors, Dopamine D1 - agonists
Receptors, Dopamine D1 - metabolism
Receptors, Dopamine D2 - metabolism
Receptors, Dopamine D3 - metabolism
Structure-Activity Relationship
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Summary:A series of new benzazepines with modification on the catecholic fragment were designed. The 8-hydroxyl group, other than the 7-hydroxyl was confirmed crucial to the interaction with the dopamine D1 receptor. Subsequent replacement of the 7-hydroxyl with benzylamino groups was found tolerable. 7-(m-Chlorophenyl)methylamino- and 7-(m- or o-tolyl)methylamino-substituted benzazepines 13b-d displayed Ki values of 270-370 nM at the D1 receptor, which were slightly more potent than that of parent compound 1. In addition, 7-(arylmethyl)amino-benzazepines 13a-c were found possessing high binding affinities less than 10 nM at the 5-HT2A receptor. Among them, the non-substituted 7-benzylamino analogue 13a was the most potent showing a Ki values of 4.5 nM at the 5-HT2A receptor and a 5-HT2A/D1 selectivity of 147.
ISSN:1768-3254
DOI:10.1016/j.ejmech.2014.07.059