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

Eur J Med Chem. 2014 Oct 6:85:16-26. doi: 10.1016/j.ejmech.2014.07.059. Epub 2014 Jul 24.

Abstract

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.

Keywords: Arylbenzazepine; Catecholic fragment; Dopamine receptor; Serotonin 5-HT(2A) receptor; Structural modification.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzazepines / agonists*
  • Benzazepines / chemistry*
  • Benzazepines / metabolism
  • CHO Cells
  • Catechols / chemistry*
  • 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

Substances

  • Benzazepines
  • Catechols
  • Receptors, Dopamine D1
  • Receptors, Dopamine D2
  • Receptors, Dopamine D3
  • catechol