Synthesis and structure-activity relationships of N-(3-phenylpropyl)-N′-benzylpiperazines: Potent ligands for σ1 and σ2 receptors

Roger I. Nahas; John R. Lever; Susan Z. Lever

doi:10.1016/j.bmc.2007.10.037

Synthesis and structure-activity relationships of N-(3-phenylpropyl)-N′-benzylpiperazines: Potent ligands for σ₁ and σ₂ receptors

Roger I. Nahas, John R. Lever, Susan Z. Lever

Research output: Contribution to journal › Article › peer-review

13 Scopus citations

Abstract

Ten N-(3-phenylpropyl)-N′-benzylpiperazines having different substituents on the benzyl moiety were synthesized and evaluated for σ₁ and σ₂ receptor binding. The σ₁ affinities were 0.37-2.80 nM, σ₂ affinities were 1.03-34.3 nM, and selectivities, as σ₂/σ₁ affinity ratios, ranged from 1.4 to 52. Three compounds tested in a phenytoin shift binding assay profiled as probable σ₁ antagonists. Quantitative structure-activity relationships depended on π_x, MR or E_s and Hammett σ values. The hydrophobicity term is negative for σ₁ binding but positive for σ₂ binding, indicating a major difference between the pharmacophores.

Original language	English (US)
Pages (from-to)	755-761
Number of pages	7
Journal	Bioorganic and Medicinal Chemistry
Volume	16
Issue number	2
DOIs	https://doi.org/10.1016/j.bmc.2007.10.037
State	Published - Jan 15 2008
Externally published	Yes

Keywords

(+)-(5α,7α,8β)-N-methyl-N-[7-(pyrrolidin-1-yl)-1-oxaspiro[4,5]dec-8-yl]benzeneacetamide
(+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine
(+)PPP
1-(2-(3,4-dimethoxy-phenyl)ethyl)-4-(3-phenylpropyl)piperazine
DAMGO
Phenylpiperazines
QSAR
Quantitative structure-activity relationship
SA4503
Sigma receptor
Structure-activity relationships
U69,593
[d-Ala,N-MePhe,Gly-ol]enkephalin

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

Access to Document

10.1016/j.bmc.2007.10.037

Cite this

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title = "Synthesis and structure-activity relationships of N-(3-phenylpropyl)-N′-benzylpiperazines: Potent ligands for σ1 and σ2 receptors",

abstract = "Ten N-(3-phenylpropyl)-N′-benzylpiperazines having different substituents on the benzyl moiety were synthesized and evaluated for σ1 and σ2 receptor binding. The σ1 affinities were 0.37-2.80 nM, σ2 affinities were 1.03-34.3 nM, and selectivities, as σ2/σ1 affinity ratios, ranged from 1.4 to 52. Three compounds tested in a phenytoin shift binding assay profiled as probable σ1 antagonists. Quantitative structure-activity relationships depended on πx, MR or Es and Hammett σ values. The hydrophobicity term is negative for σ1 binding but positive for σ2 binding, indicating a major difference between the pharmacophores.",

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author = "Nahas, {Roger I.} and Lever, {John R.} and Lever, {Susan Z.}",

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AU - Lever, John R.

AU - Lever, Susan Z.

PY - 2008/1/15

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N2 - Ten N-(3-phenylpropyl)-N′-benzylpiperazines having different substituents on the benzyl moiety were synthesized and evaluated for σ1 and σ2 receptor binding. The σ1 affinities were 0.37-2.80 nM, σ2 affinities were 1.03-34.3 nM, and selectivities, as σ2/σ1 affinity ratios, ranged from 1.4 to 52. Three compounds tested in a phenytoin shift binding assay profiled as probable σ1 antagonists. Quantitative structure-activity relationships depended on πx, MR or Es and Hammett σ values. The hydrophobicity term is negative for σ1 binding but positive for σ2 binding, indicating a major difference between the pharmacophores.

AB - Ten N-(3-phenylpropyl)-N′-benzylpiperazines having different substituents on the benzyl moiety were synthesized and evaluated for σ1 and σ2 receptor binding. The σ1 affinities were 0.37-2.80 nM, σ2 affinities were 1.03-34.3 nM, and selectivities, as σ2/σ1 affinity ratios, ranged from 1.4 to 52. Three compounds tested in a phenytoin shift binding assay profiled as probable σ1 antagonists. Quantitative structure-activity relationships depended on πx, MR or Es and Hammett σ values. The hydrophobicity term is negative for σ1 binding but positive for σ2 binding, indicating a major difference between the pharmacophores.

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