1-Phenyl-3-amino-1,2,3,4-tetrahydronaphthalenes and Related Derivatives as Ligands for the Neuromodulatory σ3 Receptor: Further Structure-Activity Relationships

Steven D. Wyrick, Raymond G. Booth, Andrew M. Myers, Constance E. Owens, Ehren C. Bucholtz, Phillip C. Hooper, Nora S. Kula, Ross J. Baldessarini, Richard Mailman

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

A series of 1-phenyl-3-amino-1,2,3,4-tetrahydronaphthalenes (1-phenyl-3-aminotetralins, PATs) previously was found to stimulate tyrosine hydroxylase activity and dopamine synthesis in rat brain through interaction with a novel σ3 receptor. Specifically, the trans-1R,3S-(-) isomer of H2-PAT showed highest affinity for σ3 receptors and also produced maximal stimulation of tyrosine hydroxylase activity and dopamine synthesis, as compared to the trans-1S,3R-(+) isomer. Affinity for σ3 receptors and functional potency at stimulating dopamine synthesis were attenuated either by altering the position or dimethyl substitution pattern of the amino group or by hydroxylating the tetralin aromatic ring. A preliminary binding model can accommodate many PAT analogs and several non-PATs with a wide range of affinities for the σ3 receptor. Here, we report the synthesis and evaluation of additional analogs in order to expand previous structure-activity relationship studies. Further molecular modifications include synthesis of 1-phenyl-1-methyl-3-amino, 1-phenyl-2-amino, 1-phenyl-3-(trimethylam-moniumyl), and 1-phenyl-3-(phenylalkyl) analogs, as well as ring-expanded tetrahydrobenzocycloheptenes. In general, the above modifications decreased σ3 receptor affinity and, in some cases, caused a reversal of the σ3 binding selectivity of transversus cis-PATs found previously. Most analogs were selective for σ3 receptors and showed little or no affinity for either σ12 or dopamine D1, D2, and D3 receptors. N-Phenylalkyl substituents, such as N-phenylethyl, however, endowed the 1-phenyl-3-aminotetralins with enhanced σ12 and dopamine receptor affinity while decreasing σ3 affinity, thus abolishing σ3 selectivity.

Original languageEnglish (US)
Pages (from-to)3857-3864
Number of pages8
JournalJournal of Medicinal Chemistry
Volume38
Issue number19
DOIs
StatePublished - Sep 1 1995

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Structure-Activity Relationship
Ligands
Dopamine
Tyrosine 3-Monooxygenase
Dopamine D3 Receptors
Dopamine D1 Receptors
Dopamine D2 Receptors
Dopamine Receptors
tetralin
2-aminotetralin
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. ; Bucholtz, Ehren C. ; Hooper, Phillip C. ; Kula, Nora S. ; Baldessarini, Ross J. ; Mailman, Richard. / 1-Phenyl-3-amino-1,2,3,4-tetrahydronaphthalenes and Related Derivatives as Ligands for the Neuromodulatory σ3 Receptor : Further Structure-Activity Relationships. In: Journal of Medicinal Chemistry. 1995 ; Vol. 38, No. 19. pp. 3857-3864.
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abstract = "A series of 1-phenyl-3-amino-1,2,3,4-tetrahydronaphthalenes (1-phenyl-3-aminotetralins, PATs) previously was found to stimulate tyrosine hydroxylase activity and dopamine synthesis in rat brain through interaction with a novel σ3 receptor. Specifically, the trans-1R,3S-(-) isomer of H2-PAT showed highest affinity for σ3 receptors and also produced maximal stimulation of tyrosine hydroxylase activity and dopamine synthesis, as compared to the trans-1S,3R-(+) isomer. Affinity for σ3 receptors and functional potency at stimulating dopamine synthesis were attenuated either by altering the position or dimethyl substitution pattern of the amino group or by hydroxylating the tetralin aromatic ring. A preliminary binding model can accommodate many PAT analogs and several non-PATs with a wide range of affinities for the σ3 receptor. Here, we report the synthesis and evaluation of additional analogs in order to expand previous structure-activity relationship studies. Further molecular modifications include synthesis of 1-phenyl-1-methyl-3-amino, 1-phenyl-2-amino, 1-phenyl-3-(trimethylam-moniumyl), and 1-phenyl-3-(phenylalkyl) analogs, as well as ring-expanded tetrahydrobenzocycloheptenes. In general, the above modifications decreased σ3 receptor affinity and, in some cases, caused a reversal of the σ3 binding selectivity of transversus cis-PATs found previously. Most analogs were selective for σ3 receptors and showed little or no affinity for either σ1\σ2 or dopamine D1, D2, and D3 receptors. N-Phenylalkyl substituents, such as N-phenylethyl, however, endowed the 1-phenyl-3-aminotetralins with enhanced σ1/σ2 and dopamine receptor affinity while decreasing σ3 affinity, thus abolishing σ3 selectivity.",
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1-Phenyl-3-amino-1,2,3,4-tetrahydronaphthalenes and Related Derivatives as Ligands for the Neuromodulatory σ3 Receptor : Further Structure-Activity Relationships. / Wyrick, Steven D.; Booth, Raymond G.; Myers, Andrew M.; Owens, Constance E.; Bucholtz, Ehren C.; Hooper, Phillip C.; Kula, Nora S.; Baldessarini, Ross J.; Mailman, Richard.

In: Journal of Medicinal Chemistry, Vol. 38, No. 19, 01.09.1995, p. 3857-3864.

Research output: Contribution to journalArticle

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T1 - 1-Phenyl-3-amino-1,2,3,4-tetrahydronaphthalenes and Related Derivatives as Ligands for the Neuromodulatory σ3 Receptor

T2 - Further Structure-Activity Relationships

AU - Wyrick, Steven D.

AU - Booth, Raymond G.

AU - Myers, Andrew M.

AU - Owens, Constance E.

AU - Bucholtz, Ehren C.

AU - Hooper, Phillip C.

AU - Kula, Nora S.

AU - Baldessarini, Ross J.

AU - Mailman, Richard

PY - 1995/9/1

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N2 - A series of 1-phenyl-3-amino-1,2,3,4-tetrahydronaphthalenes (1-phenyl-3-aminotetralins, PATs) previously was found to stimulate tyrosine hydroxylase activity and dopamine synthesis in rat brain through interaction with a novel σ3 receptor. Specifically, the trans-1R,3S-(-) isomer of H2-PAT showed highest affinity for σ3 receptors and also produced maximal stimulation of tyrosine hydroxylase activity and dopamine synthesis, as compared to the trans-1S,3R-(+) isomer. Affinity for σ3 receptors and functional potency at stimulating dopamine synthesis were attenuated either by altering the position or dimethyl substitution pattern of the amino group or by hydroxylating the tetralin aromatic ring. A preliminary binding model can accommodate many PAT analogs and several non-PATs with a wide range of affinities for the σ3 receptor. Here, we report the synthesis and evaluation of additional analogs in order to expand previous structure-activity relationship studies. Further molecular modifications include synthesis of 1-phenyl-1-methyl-3-amino, 1-phenyl-2-amino, 1-phenyl-3-(trimethylam-moniumyl), and 1-phenyl-3-(phenylalkyl) analogs, as well as ring-expanded tetrahydrobenzocycloheptenes. In general, the above modifications decreased σ3 receptor affinity and, in some cases, caused a reversal of the σ3 binding selectivity of transversus cis-PATs found previously. Most analogs were selective for σ3 receptors and showed little or no affinity for either σ1\σ2 or dopamine D1, D2, and D3 receptors. N-Phenylalkyl substituents, such as N-phenylethyl, however, endowed the 1-phenyl-3-aminotetralins with enhanced σ1/σ2 and dopamine receptor affinity while decreasing σ3 affinity, thus abolishing σ3 selectivity.

AB - A series of 1-phenyl-3-amino-1,2,3,4-tetrahydronaphthalenes (1-phenyl-3-aminotetralins, PATs) previously was found to stimulate tyrosine hydroxylase activity and dopamine synthesis in rat brain through interaction with a novel σ3 receptor. Specifically, the trans-1R,3S-(-) isomer of H2-PAT showed highest affinity for σ3 receptors and also produced maximal stimulation of tyrosine hydroxylase activity and dopamine synthesis, as compared to the trans-1S,3R-(+) isomer. Affinity for σ3 receptors and functional potency at stimulating dopamine synthesis were attenuated either by altering the position or dimethyl substitution pattern of the amino group or by hydroxylating the tetralin aromatic ring. A preliminary binding model can accommodate many PAT analogs and several non-PATs with a wide range of affinities for the σ3 receptor. Here, we report the synthesis and evaluation of additional analogs in order to expand previous structure-activity relationship studies. Further molecular modifications include synthesis of 1-phenyl-1-methyl-3-amino, 1-phenyl-2-amino, 1-phenyl-3-(trimethylam-moniumyl), and 1-phenyl-3-(phenylalkyl) analogs, as well as ring-expanded tetrahydrobenzocycloheptenes. In general, the above modifications decreased σ3 receptor affinity and, in some cases, caused a reversal of the σ3 binding selectivity of transversus cis-PATs found previously. Most analogs were selective for σ3 receptors and showed little or no affinity for either σ1\σ2 or dopamine D1, D2, and D3 receptors. N-Phenylalkyl substituents, such as N-phenylethyl, however, endowed the 1-phenyl-3-aminotetralins with enhanced σ1/σ2 and dopamine receptor affinity while decreasing σ3 affinity, thus abolishing σ3 selectivity.

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