Synthesis and Pharmacological Evaluation of 1-Phenyl-3-amino-1,2,3,4-tetrahydronaphthalenes as Ligands for a Novel Receptor with σ-like Neuromodulatory Activity

Steven D. Wyrick, Raymond G. Booth, Andrew M. Myers, Constance E. Owens, Nora S. Kula, Ross J. Baldessarini, Andrew T. McPhail, Richard B. Mailman

Research output: Contribution to journalArticle

44 Citations (Scopus)

Abstract

Certainnovel 1-phenyl-3-amino-1,2,3,4-tetrahydronaphthalenes (1-phenyl-3-aminotetralins, PATs) produced stimulation (ca. 30% above basal levels) of tyrosine hydroxylase (TH) activity at 0.1 µM concentrations in rodent brain tissue. This effect on TH was blocked by the putative σ-receptor antagonist BMY-14802, suggesting involvement of a novel neuromodulatory σ-like receptor. Within the new phenylaminotetralin series, a correlation was found between the ability to stimulate TH and the potency to compete for binding sites labeled by (±)-[3H]1-phenyl-3-(N,N-dimethylamino)-6-chloro-7-hydroxy-1,2,3,4-tetrahydronaphthalene {[3H](±)-4}. trans-Catechol analogs had low affinity for [3H]4 sites, and although they inhibited TH activity, this effect was not blocked by known σ or dopamine antagonists. Analogs with dihydroxy substituents (catechols), as well as nitrogen substituents larger than methyl, had little affinity for [3H]4 binding sites and did not significantly affect TH activity. The pharmacology of the [3H]4 binding site is unique from that of any known σ or dopamine receptor, thus the effects appear to be mediated by a previously uncharacterized binding site/receptor. The site has stereoselectivity for the (1R,3S)-(−)-isomer of 1-phenyl-3-(N,N-dimethylamino)-1,2,3,4-tetrahydronaphthalene; this isomer is also more active at stimulating TH. Thus, certain 1-phenyl-3-amino-1,2,3,4-tetrahydronaphthalenes appear to be selective probes of a novel receptor type that mediates σ-like neuromodulatory activity and may have pharmacotherapeutic utility in conditions in which modulation of dopamine function is important.

Original languageEnglish (US)
Pages (from-to)2542-2551
Number of pages10
JournalJournal of Medicinal Chemistry
Volume36
Issue number17
DOIs
StatePublished - Jan 1 1993

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Tyrosine 3-Monooxygenase
Pharmacology
Ligands
Binding Sites
Catechols
Dopamine Antagonists
Dopamine Receptors
tetralin
Rodentia
Dopamine
Nitrogen
Brain

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

Cite this

Wyrick, Steven D. ; Booth, Raymond G. ; Myers, Andrew M. ; Owens, Constance E. ; Kula, Nora S. ; Baldessarini, Ross J. ; McPhail, Andrew T. ; Mailman, Richard B. / Synthesis and Pharmacological Evaluation of 1-Phenyl-3-amino-1,2,3,4-tetrahydronaphthalenes as Ligands for a Novel Receptor with σ-like Neuromodulatory Activity. In: Journal of Medicinal Chemistry. 1993 ; Vol. 36, No. 17. pp. 2542-2551.
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abstract = "Certainnovel 1-phenyl-3-amino-1,2,3,4-tetrahydronaphthalenes (1-phenyl-3-aminotetralins, PATs) produced stimulation (ca. 30{\%} above basal levels) of tyrosine hydroxylase (TH) activity at 0.1 µM concentrations in rodent brain tissue. This effect on TH was blocked by the putative σ-receptor antagonist BMY-14802, suggesting involvement of a novel neuromodulatory σ-like receptor. Within the new phenylaminotetralin series, a correlation was found between the ability to stimulate TH and the potency to compete for binding sites labeled by (±)-[3H]1-phenyl-3-(N,N-dimethylamino)-6-chloro-7-hydroxy-1,2,3,4-tetrahydronaphthalene {[3H](±)-4}. trans-Catechol analogs had low affinity for [3H]4 sites, and although they inhibited TH activity, this effect was not blocked by known σ or dopamine antagonists. Analogs with dihydroxy substituents (catechols), as well as nitrogen substituents larger than methyl, had little affinity for [3H]4 binding sites and did not significantly affect TH activity. The pharmacology of the [3H]4 binding site is unique from that of any known σ or dopamine receptor, thus the effects appear to be mediated by a previously uncharacterized binding site/receptor. The site has stereoselectivity for the (1R,3S)-(−)-isomer of 1-phenyl-3-(N,N-dimethylamino)-1,2,3,4-tetrahydronaphthalene; this isomer is also more active at stimulating TH. Thus, certain 1-phenyl-3-amino-1,2,3,4-tetrahydronaphthalenes appear to be selective probes of a novel receptor type that mediates σ-like neuromodulatory activity and may have pharmacotherapeutic utility in conditions in which modulation of dopamine function is important.",
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Synthesis and Pharmacological Evaluation of 1-Phenyl-3-amino-1,2,3,4-tetrahydronaphthalenes as Ligands for a Novel Receptor with σ-like Neuromodulatory Activity. / Wyrick, Steven D.; Booth, Raymond G.; Myers, Andrew M.; Owens, Constance E.; Kula, Nora S.; Baldessarini, Ross J.; McPhail, Andrew T.; Mailman, Richard B.

In: Journal of Medicinal Chemistry, Vol. 36, No. 17, 01.01.1993, p. 2542-2551.

Research output: Contribution to journalArticle

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AU - Wyrick, Steven D.

AU - Booth, Raymond G.

AU - Myers, Andrew M.

AU - Owens, Constance E.

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AU - Mailman, Richard B.

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AB - Certainnovel 1-phenyl-3-amino-1,2,3,4-tetrahydronaphthalenes (1-phenyl-3-aminotetralins, PATs) produced stimulation (ca. 30% above basal levels) of tyrosine hydroxylase (TH) activity at 0.1 µM concentrations in rodent brain tissue. This effect on TH was blocked by the putative σ-receptor antagonist BMY-14802, suggesting involvement of a novel neuromodulatory σ-like receptor. Within the new phenylaminotetralin series, a correlation was found between the ability to stimulate TH and the potency to compete for binding sites labeled by (±)-[3H]1-phenyl-3-(N,N-dimethylamino)-6-chloro-7-hydroxy-1,2,3,4-tetrahydronaphthalene {[3H](±)-4}. trans-Catechol analogs had low affinity for [3H]4 sites, and although they inhibited TH activity, this effect was not blocked by known σ or dopamine antagonists. Analogs with dihydroxy substituents (catechols), as well as nitrogen substituents larger than methyl, had little affinity for [3H]4 binding sites and did not significantly affect TH activity. The pharmacology of the [3H]4 binding site is unique from that of any known σ or dopamine receptor, thus the effects appear to be mediated by a previously uncharacterized binding site/receptor. The site has stereoselectivity for the (1R,3S)-(−)-isomer of 1-phenyl-3-(N,N-dimethylamino)-1,2,3,4-tetrahydronaphthalene; this isomer is also more active at stimulating TH. Thus, certain 1-phenyl-3-amino-1,2,3,4-tetrahydronaphthalenes appear to be selective probes of a novel receptor type that mediates σ-like neuromodulatory activity and may have pharmacotherapeutic utility in conditions in which modulation of dopamine function is important.

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