Structural manipulation on the catecholic fragment of dopamine D1 receptor agonist 1-phenyl-N-methyl-benzazepines

•Aryl-N3-benzazepine framework is the prototypical dopamine D1 receptor ligand.•Our study directly focused on modification of the metabolic site-catechol moiety.•Compounds 13b–d displayed Ki values of 270–370 nM at the D1 receptor.•Most compounds possess high affinity less than 10 nM at the 5-HT2A receptor.•13a was the most potent with a Ki value of 4.5 nM at the 5-HT2A receptor.

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.

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