(±)-3-[4'-(N,N-dimethylamino)cinnamyl]benzazepine analogs: Novel dopamine D1 receptor antagonists

Jamshed H. Shah, Richard H. Kline, Beth Geter-Douglass, Sari Izenwasser, Jeffrey M. Witkin, Amy Hauck Newman

Research output: Contribution to journalArticlepeer-review

7 Scopus citations


Neurochemical studies and structure-activity relationships of dopamine D1 receptor ligands suggest that their intrinsic activity may depend on the conformational state or binding site at which they interact on the receptor protein. Important differences in the modes of binding of these ligands may confer their agonist, partial agonist, or antagonist properties. In an effort to develop novel dopamine D1 antagonists and investigate the D1 antagonist pharmacophore, a series of (±)-(N-alkylamino)benzazepines were prepared in which (±)-7-chloro-8-hydroxy-3-[6-(N,N-dimethylamino)hexyl]-1- phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (1) demonstrated the highest binding affinity (K(i) = 49.3 nM) and selectivity to dopamine D1 receptors. This compound inhibited dopamine-stimulated adenylyl cyclase, in rat caudate, confirming a D1 receptor antagonist profile. From this initial series of N-alkylamino-substituted benzazepines, structure activity relationships suggested that the terminal amino function was necessary for optimal binding affinity and selectivity at D1 vs D2 sites. Further, addition of this side chain to the D1 agonist pharmacophore (e.g., 7,8- dihydroxy-3-[4-(N,N-dimethylamino)butyl]-1-phenyl-2,3,4,5-tetrahydro-1H-3- benzazepine) greatly decreased binding affinity at D1 receptors. These data suggested that a binding domain that may be unique to the D1 antagonists may have been identified. In an attempt to exploit an apparent amine- accepting binding domain on the D1 receptor, a series of (±)-3-[4'-(N,N- dimethylamino)cinnamyl]benzazepine analogs was designed and prepared, as D1 antagonists. In this series, (±)-7-chloro-8-hydroxy-3-[4'-(N,N- dimethylamino)cinnamyl]-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (6a) showed the highest binding affinity (K(i) = 60.3 nM) for dopamine D1 receptors. Compound 6a was a potent dopamine D1 antagonist as evidenced by its ability to block dopamine-stimulated adenylyl cyclase activity in rat caudate (predicted K(i) value = 18.4 nM). Molecular modeling studies demonstrated that the most potent and selective dopamine D1 antagonists, in both series, contained terminal amino groups 8-9 Å away from the 3-position benzazepine nitrogen. Compounds that lacked a terminal amine function or where this moiety was less than 7 Å away from the benzazepine nitrogen demonstrated significantly lower binding affinities. Therefore, this series of (±)-3-[4'-(N,N-dimethylamino)cinnamyl]benzazepines also appears to be identifying an amine-accepting binding domain on the dopamine D1 receptor protein that may be further explored for the development of novel dopamine D1 antagonists.

Original languageEnglish (US)
Pages (from-to)3423-3428
Number of pages6
JournalJournal of Medicinal Chemistry
Issue number17
StatePublished - Jan 1 1996
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery


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