Synthesis and pharmacological characterization of 1-phenyl-, 4-phenyl-, and 1-benzyl-1, 2, 3, 4-tetrahydroisoquinolines as dopamine receptor ligands

Paul S. Charifson, Steven D. Wyrick, J. Phillip Bowen, Darryl L. McDougald, Andrew J. Hoffman, Rosa M. Ademe Simmons, Richard Mailman

Research output: Contribution to journalArticle

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Abstract

A series of 1-phenyl-, 4-phenyl-, and 1-benzyl-1, 2, 3, 4-tetrahydroisoquinolines have been prepared as ring-contracted analogues of the prototypical D1dopamine receptor antagonist SCH23390 [(R)-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2, 3, 4, 5-tetrahydro-1H-3-benzazepine]. The affinity and selectivity of these isoquinolines for receptors was determined by three biochemical endpoints in membrane homogenates prepared from rat corpus striatum: the potency to compete for [3H]SCH23390 binding sites; the potency to compete for [3H]spiperone (a D2receptor ligand) binding sites; and effects on dopamine-stimulated adenylate cyclase. Competitive binding measurements at D1sites showed SCH23390 to possess the highest affinity, followed by 1-phenyl > 1-benzyl > 4-phenyl for the isoquinolines. These results were highly correlated with the ability of the test compounds to antagonize dopamine-stimulated adenylate cyclase (r = 0.98). None of the compounds alone stimulated cAMP formation at concentrations of 10 nM to 100 μM. D2competition binding showed the 1-benzyl derivative to possess the highest affinity, followed by 4-phenyl > SCH23390 > 1-phenyl. The tertiary 1-phenyl derivative was more potent than the secondary 1-phenyl analogue in all assays. Interestingly, resolution and single-crystal X-ray analysis of the tertiary N-methyl-1-phenyltetrahydroisoquinoline showed the most active enantiomer to possess the S absolute configuration, in contrast to the benzazepine (R)-SCH23390.

Original languageEnglish (US)
Pages (from-to)1941-1946
Number of pages6
JournalJournal of Medicinal Chemistry
Volume31
Issue number10
DOIs
StatePublished - Feb 1 1988

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Dopamine Receptors
Pharmacology
Ligands
Adenylyl Cyclases
Dopamine
Isoquinolines
Benzazepines
Binding Sites
Corpus Striatum
Spiperone
Competitive Binding
X-Rays
SCH 23390
1,2,3,4-tetrahydro-1-(phenylmethyl)isoquinoline
Membranes

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

Cite this

Charifson, Paul S. ; Wyrick, Steven D. ; Phillip Bowen, J. ; McDougald, Darryl L. ; Hoffman, Andrew J. ; Ademe Simmons, Rosa M. ; Mailman, Richard. / Synthesis and pharmacological characterization of 1-phenyl-, 4-phenyl-, and 1-benzyl-1, 2, 3, 4-tetrahydroisoquinolines as dopamine receptor ligands. In: Journal of Medicinal Chemistry. 1988 ; Vol. 31, No. 10. pp. 1941-1946.
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abstract = "A series of 1-phenyl-, 4-phenyl-, and 1-benzyl-1, 2, 3, 4-tetrahydroisoquinolines have been prepared as ring-contracted analogues of the prototypical D1dopamine receptor antagonist SCH23390 [(R)-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2, 3, 4, 5-tetrahydro-1H-3-benzazepine]. The affinity and selectivity of these isoquinolines for receptors was determined by three biochemical endpoints in membrane homogenates prepared from rat corpus striatum: the potency to compete for [3H]SCH23390 binding sites; the potency to compete for [3H]spiperone (a D2receptor ligand) binding sites; and effects on dopamine-stimulated adenylate cyclase. Competitive binding measurements at D1sites showed SCH23390 to possess the highest affinity, followed by 1-phenyl > 1-benzyl > 4-phenyl for the isoquinolines. These results were highly correlated with the ability of the test compounds to antagonize dopamine-stimulated adenylate cyclase (r = 0.98). None of the compounds alone stimulated cAMP formation at concentrations of 10 nM to 100 μM. D2competition binding showed the 1-benzyl derivative to possess the highest affinity, followed by 4-phenyl > SCH23390 > 1-phenyl. The tertiary 1-phenyl derivative was more potent than the secondary 1-phenyl analogue in all assays. Interestingly, resolution and single-crystal X-ray analysis of the tertiary N-methyl-1-phenyltetrahydroisoquinoline showed the most active enantiomer to possess the S absolute configuration, in contrast to the benzazepine (R)-SCH23390.",
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Synthesis and pharmacological characterization of 1-phenyl-, 4-phenyl-, and 1-benzyl-1, 2, 3, 4-tetrahydroisoquinolines as dopamine receptor ligands. / Charifson, Paul S.; Wyrick, Steven D.; Phillip Bowen, J.; McDougald, Darryl L.; Hoffman, Andrew J.; Ademe Simmons, Rosa M.; Mailman, Richard.

In: Journal of Medicinal Chemistry, Vol. 31, No. 10, 01.02.1988, p. 1941-1946.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Synthesis and pharmacological characterization of 1-phenyl-, 4-phenyl-, and 1-benzyl-1, 2, 3, 4-tetrahydroisoquinolines as dopamine receptor ligands

AU - Charifson, Paul S.

AU - Wyrick, Steven D.

AU - Phillip Bowen, J.

AU - McDougald, Darryl L.

AU - Hoffman, Andrew J.

AU - Ademe Simmons, Rosa M.

AU - Mailman, Richard

PY - 1988/2/1

Y1 - 1988/2/1

N2 - A series of 1-phenyl-, 4-phenyl-, and 1-benzyl-1, 2, 3, 4-tetrahydroisoquinolines have been prepared as ring-contracted analogues of the prototypical D1dopamine receptor antagonist SCH23390 [(R)-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2, 3, 4, 5-tetrahydro-1H-3-benzazepine]. The affinity and selectivity of these isoquinolines for receptors was determined by three biochemical endpoints in membrane homogenates prepared from rat corpus striatum: the potency to compete for [3H]SCH23390 binding sites; the potency to compete for [3H]spiperone (a D2receptor ligand) binding sites; and effects on dopamine-stimulated adenylate cyclase. Competitive binding measurements at D1sites showed SCH23390 to possess the highest affinity, followed by 1-phenyl > 1-benzyl > 4-phenyl for the isoquinolines. These results were highly correlated with the ability of the test compounds to antagonize dopamine-stimulated adenylate cyclase (r = 0.98). None of the compounds alone stimulated cAMP formation at concentrations of 10 nM to 100 μM. D2competition binding showed the 1-benzyl derivative to possess the highest affinity, followed by 4-phenyl > SCH23390 > 1-phenyl. The tertiary 1-phenyl derivative was more potent than the secondary 1-phenyl analogue in all assays. Interestingly, resolution and single-crystal X-ray analysis of the tertiary N-methyl-1-phenyltetrahydroisoquinoline showed the most active enantiomer to possess the S absolute configuration, in contrast to the benzazepine (R)-SCH23390.

AB - A series of 1-phenyl-, 4-phenyl-, and 1-benzyl-1, 2, 3, 4-tetrahydroisoquinolines have been prepared as ring-contracted analogues of the prototypical D1dopamine receptor antagonist SCH23390 [(R)-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2, 3, 4, 5-tetrahydro-1H-3-benzazepine]. The affinity and selectivity of these isoquinolines for receptors was determined by three biochemical endpoints in membrane homogenates prepared from rat corpus striatum: the potency to compete for [3H]SCH23390 binding sites; the potency to compete for [3H]spiperone (a D2receptor ligand) binding sites; and effects on dopamine-stimulated adenylate cyclase. Competitive binding measurements at D1sites showed SCH23390 to possess the highest affinity, followed by 1-phenyl > 1-benzyl > 4-phenyl for the isoquinolines. These results were highly correlated with the ability of the test compounds to antagonize dopamine-stimulated adenylate cyclase (r = 0.98). None of the compounds alone stimulated cAMP formation at concentrations of 10 nM to 100 μM. D2competition binding showed the 1-benzyl derivative to possess the highest affinity, followed by 4-phenyl > SCH23390 > 1-phenyl. The tertiary 1-phenyl derivative was more potent than the secondary 1-phenyl analogue in all assays. Interestingly, resolution and single-crystal X-ray analysis of the tertiary N-methyl-1-phenyltetrahydroisoquinoline showed the most active enantiomer to possess the S absolute configuration, in contrast to the benzazepine (R)-SCH23390.

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