Synthesis and Evaluation of 6,7-Dihydroxy-2,3,4,8,9,13b-hexahydro-1H-benzo[6,7]cyclohepta[1,2,3-ef][3]benzazepine, 6,7-Dihydroxy-1,2,3,4,8,12b-hexahydroanthr[10,4a,4-cd]azepine, and 10-(Aminomethyl)-9,10-dihydro-1,2-dihydroxyanthracene as Conformationally Restricted Analogs of β-Phenyldopamine

Scott E. Snyder, Felix A. Aviles-Garay, Ratna Chakraborti, David E. Nichols, Val J. Watts, Richard Mailman

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Abstract

The present study was designed to define the geometry of the hydrophobic accessory region for binding of dopamine D1 receptor ligands and to assess the relative importance of ethylamine side chain conformation for receptor affinity. Three compounds, 6,7-dihydroxy-2,3,4,8,9,13b-hexahydro-1H-benzo[6,7]cyclohepta[1,2,3-ef][3]benzazepine, 4, 6,7-dihydroxy-1,2,3,4,8,12b-hexahydroanthr[10,4a,4-cd]azepine, 5, and 10-(aminomethyl)-9,10-dihydro-1,2-dihydroxyanthracene, 6, were synthesized as conformationally restricted analogs of β-phenyldopamine. Molecular modeling studies were performed to compare these three compounds with the high-affinity D1 agonists dihydrexidine (DHX), 2, and SKF 38393, 3. The β-phenyl moieties in the target compounds are constrained by means of either an ethyl (4) or methylene (5 and 6) bridge. The compounds adopt minimum-energy conformations in which the β-phenyl group is approximately -22° (4), -12° (5), and -30° (6) from coplanarity with the catechol ring. These compounds also embody either a freely rotating (6) or a rigidified gauche (4 and 5) rotameric conformation of the dopamine ethylamine side chain, the latter nearly perfectly superimposible on the benzazepine portion of SKF 38393. Radioligand competition experiments showed that compounds 4,5, and 6 have only micromolar affinity for both the D1 and D2 dopamine receptor subtypes. The low affinity of 4-6, relative to 2 and 3, may be due to improper orientation of the β-phenyl moiety and provides important information about the three-dimensional orientation of the hydrophobic accessory binding domain of the dopamine D1 receptor. In addition, the negligible affinity of 6, as compared to 2 and 3, indicates that the rotameric positioning of the ethylamine side chain may not be a primary determinant of receptor affinity.

Original languageEnglish (US)
Pages (from-to)2395-2409
Number of pages15
JournalJournal of Medicinal Chemistry
Volume38
Issue number13
DOIs
StatePublished - Jun 1 1995

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Dopamine D1 Receptors
2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine
Benzazepines
Dopamine D2 Receptors
Dopamine
Ligands
6,7-dihydroxy-2,3,4,8,9,13b-hexahydro-1H-benzo(6,7)cyclohepta(1,2,3-ef)(3)benzazepine
6,7-dihydroxy-1,2,3,4,8,12b-hexahydroanthr(10,4a,4-cd)azepine
10-(aminomethyl)-9,10-dihydro-1,2-dihydroxyanthracene
ethylamine

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

Cite this

@article{8d48b62f0cf843f888cc11f287d08f4d,
title = "Synthesis and Evaluation of 6,7-Dihydroxy-2,3,4,8,9,13b-hexahydro-1H-benzo[6,7]cyclohepta[1,2,3-ef][3]benzazepine, 6,7-Dihydroxy-1,2,3,4,8,12b-hexahydroanthr[10,4a,4-cd]azepine, and 10-(Aminomethyl)-9,10-dihydro-1,2-dihydroxyanthracene as Conformationally Restricted Analogs of β-Phenyldopamine",
abstract = "The present study was designed to define the geometry of the hydrophobic accessory region for binding of dopamine D1 receptor ligands and to assess the relative importance of ethylamine side chain conformation for receptor affinity. Three compounds, 6,7-dihydroxy-2,3,4,8,9,13b-hexahydro-1H-benzo[6,7]cyclohepta[1,2,3-ef][3]benzazepine, 4, 6,7-dihydroxy-1,2,3,4,8,12b-hexahydroanthr[10,4a,4-cd]azepine, 5, and 10-(aminomethyl)-9,10-dihydro-1,2-dihydroxyanthracene, 6, were synthesized as conformationally restricted analogs of β-phenyldopamine. Molecular modeling studies were performed to compare these three compounds with the high-affinity D1 agonists dihydrexidine (DHX), 2, and SKF 38393, 3. The β-phenyl moieties in the target compounds are constrained by means of either an ethyl (4) or methylene (5 and 6) bridge. The compounds adopt minimum-energy conformations in which the β-phenyl group is approximately -22° (4), -12° (5), and -30° (6) from coplanarity with the catechol ring. These compounds also embody either a freely rotating (6) or a rigidified gauche (4 and 5) rotameric conformation of the dopamine ethylamine side chain, the latter nearly perfectly superimposible on the benzazepine portion of SKF 38393. Radioligand competition experiments showed that compounds 4,5, and 6 have only micromolar affinity for both the D1 and D2 dopamine receptor subtypes. The low affinity of 4-6, relative to 2 and 3, may be due to improper orientation of the β-phenyl moiety and provides important information about the three-dimensional orientation of the hydrophobic accessory binding domain of the dopamine D1 receptor. In addition, the negligible affinity of 6, as compared to 2 and 3, indicates that the rotameric positioning of the ethylamine side chain may not be a primary determinant of receptor affinity.",
author = "Snyder, {Scott E.} and Aviles-Garay, {Felix A.} and Ratna Chakraborti and Nichols, {David E.} and Watts, {Val J.} and Richard Mailman",
year = "1995",
month = "6",
day = "1",
doi = "10.1021/jm00013a015",
language = "English (US)",
volume = "38",
pages = "2395--2409",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "13",

}

TY - JOUR

T1 - Synthesis and Evaluation of 6,7-Dihydroxy-2,3,4,8,9,13b-hexahydro-1H-benzo[6,7]cyclohepta[1,2,3-ef][3]benzazepine, 6,7-Dihydroxy-1,2,3,4,8,12b-hexahydroanthr[10,4a,4-cd]azepine, and 10-(Aminomethyl)-9,10-dihydro-1,2-dihydroxyanthracene as Conformationally Restricted Analogs of β-Phenyldopamine

AU - Snyder, Scott E.

AU - Aviles-Garay, Felix A.

AU - Chakraborti, Ratna

AU - Nichols, David E.

AU - Watts, Val J.

AU - Mailman, Richard

PY - 1995/6/1

Y1 - 1995/6/1

N2 - The present study was designed to define the geometry of the hydrophobic accessory region for binding of dopamine D1 receptor ligands and to assess the relative importance of ethylamine side chain conformation for receptor affinity. Three compounds, 6,7-dihydroxy-2,3,4,8,9,13b-hexahydro-1H-benzo[6,7]cyclohepta[1,2,3-ef][3]benzazepine, 4, 6,7-dihydroxy-1,2,3,4,8,12b-hexahydroanthr[10,4a,4-cd]azepine, 5, and 10-(aminomethyl)-9,10-dihydro-1,2-dihydroxyanthracene, 6, were synthesized as conformationally restricted analogs of β-phenyldopamine. Molecular modeling studies were performed to compare these three compounds with the high-affinity D1 agonists dihydrexidine (DHX), 2, and SKF 38393, 3. The β-phenyl moieties in the target compounds are constrained by means of either an ethyl (4) or methylene (5 and 6) bridge. The compounds adopt minimum-energy conformations in which the β-phenyl group is approximately -22° (4), -12° (5), and -30° (6) from coplanarity with the catechol ring. These compounds also embody either a freely rotating (6) or a rigidified gauche (4 and 5) rotameric conformation of the dopamine ethylamine side chain, the latter nearly perfectly superimposible on the benzazepine portion of SKF 38393. Radioligand competition experiments showed that compounds 4,5, and 6 have only micromolar affinity for both the D1 and D2 dopamine receptor subtypes. The low affinity of 4-6, relative to 2 and 3, may be due to improper orientation of the β-phenyl moiety and provides important information about the three-dimensional orientation of the hydrophobic accessory binding domain of the dopamine D1 receptor. In addition, the negligible affinity of 6, as compared to 2 and 3, indicates that the rotameric positioning of the ethylamine side chain may not be a primary determinant of receptor affinity.

AB - The present study was designed to define the geometry of the hydrophobic accessory region for binding of dopamine D1 receptor ligands and to assess the relative importance of ethylamine side chain conformation for receptor affinity. Three compounds, 6,7-dihydroxy-2,3,4,8,9,13b-hexahydro-1H-benzo[6,7]cyclohepta[1,2,3-ef][3]benzazepine, 4, 6,7-dihydroxy-1,2,3,4,8,12b-hexahydroanthr[10,4a,4-cd]azepine, 5, and 10-(aminomethyl)-9,10-dihydro-1,2-dihydroxyanthracene, 6, were synthesized as conformationally restricted analogs of β-phenyldopamine. Molecular modeling studies were performed to compare these three compounds with the high-affinity D1 agonists dihydrexidine (DHX), 2, and SKF 38393, 3. The β-phenyl moieties in the target compounds are constrained by means of either an ethyl (4) or methylene (5 and 6) bridge. The compounds adopt minimum-energy conformations in which the β-phenyl group is approximately -22° (4), -12° (5), and -30° (6) from coplanarity with the catechol ring. These compounds also embody either a freely rotating (6) or a rigidified gauche (4 and 5) rotameric conformation of the dopamine ethylamine side chain, the latter nearly perfectly superimposible on the benzazepine portion of SKF 38393. Radioligand competition experiments showed that compounds 4,5, and 6 have only micromolar affinity for both the D1 and D2 dopamine receptor subtypes. The low affinity of 4-6, relative to 2 and 3, may be due to improper orientation of the β-phenyl moiety and provides important information about the three-dimensional orientation of the hydrophobic accessory binding domain of the dopamine D1 receptor. In addition, the negligible affinity of 6, as compared to 2 and 3, indicates that the rotameric positioning of the ethylamine side chain may not be a primary determinant of receptor affinity.

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