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Synthesis and receptor affinities of some conformationally restricted analogues of the dopamine D1 selective ligand (5R)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl- 1H-3-benzazepin-7-ol.

Publication ,  Journal Article
Berger, JG; Chang, WK; Clader, JW; Hou, D; Chipkin, RE; McPhail, AT
Published in: Journal of medicinal chemistry
August 1989

The synthesis of a structurally novel series of 6,6a,7,8,9,13b-hexahydro-5H-benzo[d]naphtho[2,1-b]azepines (2), conformationally restricted analogues of the dopamine D1 antagonist (5R)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepin -7-ol (SCH 23390, 1c), is described. Affinity for D1 receptors was determined by competition for rat striatal binding sites labeled by [3H]SCH 23390; affinity for D2 receptors was similarly determined by competition experiments using [3H]spiperone. Compounds in this series having the B/C-trans ring junction (2b and related analogues), where the D ring is unequivocally fixed in an equatorial orientation, possess considerably more D1 receptor affinity and selectivity vs the D2 receptor than the conformationally mobile cis stereoisomers (2a), thus leading to the conclusion that axial substituents at the 4- or 5-positions of the benzazepine nucleus are detrimental to D1 receptor affinity. Resolution and X-ray analysis demonstrated that D1 receptor affinity was preferentially associated with the (-)-6aS,13bR enantiomer of 2b.

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Published In

Journal of medicinal chemistry

DOI

EISSN

1520-4804

ISSN

0022-2623

Publication Date

August 1989

Volume

32

Issue

8

Start / End Page

1913 / 1921

Related Subject Headings

  • Structure-Activity Relationship
  • Stereoisomerism
  • Receptors, Dopamine
  • Rats, Inbred Strains
  • Rats
  • Molecular Conformation
  • Models, Molecular
  • Medicinal & Biomolecular Chemistry
  • Male
  • In Vitro Techniques
 

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Berger, J. G., Chang, W. K., Clader, J. W., Hou, D., Chipkin, R. E., & McPhail, A. T. (1989). Synthesis and receptor affinities of some conformationally restricted analogues of the dopamine D1 selective ligand (5R)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl- 1H-3-benzazepin-7-ol. Journal of Medicinal Chemistry, 32(8), 1913–1921. https://doi.org/10.1021/jm00128a038
Berger, J. G., W. K. Chang, J. W. Clader, D. Hou, R. E. Chipkin, and A. T. McPhail. “Synthesis and receptor affinities of some conformationally restricted analogues of the dopamine D1 selective ligand (5R)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl- 1H-3-benzazepin-7-ol.Journal of Medicinal Chemistry 32, no. 8 (August 1989): 1913–21. https://doi.org/10.1021/jm00128a038.
Berger, J. G., et al. “Synthesis and receptor affinities of some conformationally restricted analogues of the dopamine D1 selective ligand (5R)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl- 1H-3-benzazepin-7-ol.Journal of Medicinal Chemistry, vol. 32, no. 8, Aug. 1989, pp. 1913–21. Epmc, doi:10.1021/jm00128a038.
Journal cover image

Published In

Journal of medicinal chemistry

DOI

EISSN

1520-4804

ISSN

0022-2623

Publication Date

August 1989

Volume

32

Issue

8

Start / End Page

1913 / 1921

Related Subject Headings

  • Structure-Activity Relationship
  • Stereoisomerism
  • Receptors, Dopamine
  • Rats, Inbred Strains
  • Rats
  • Molecular Conformation
  • Models, Molecular
  • Medicinal & Biomolecular Chemistry
  • Male
  • In Vitro Techniques