Design, Synthesis, and Structure−Affinity Relationships of Regioisomeric N-Benzyl Alkyl Ether Piperazine Derivatives as σ-1 Receptor Ligands

A series of N-(benzofuran-2-ylmethyl)-N′-benzylpiperazines bearing alkyl or fluoroalkyl aryl ethers were synthesized and evaluated at various central nervous system receptors. Examination of in vitro σ1 {[3H](+)-pentazocine} and σ2 ([3H]DTG) receptor binding profiles of piperazines 11−13 and 25−36 r...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2010-08, Vol.53 (16), p.6228-6239
Main Authors: Moussa, Iman A, Banister, Samuel D, Beinat, Corinne, Giboureau, Nicolas, Reynolds, Aaron J, Kassiou, Michael
Format: Article
Language:English
Subjects:
Animals
Benzofurans - chemical synthesis
Benzofurans - chemistry
Benzofurans - pharmacokinetics
Binding, Competitive
Brain - metabolism
Carbon Radioisotopes
Ethers - chemical synthesis
Ethers - chemistry
Ethers - pharmacokinetics
In Vitro Techniques
Ligands
Papio
PC12 Cells
Piperazines - chemical synthesis
Piperazines - chemistry
Piperazines - pharmacokinetics
Positron-Emission Tomography
Radioligand Assay
Radiopharmaceuticals - chemical synthesis
Radiopharmaceuticals - chemistry
Radiopharmaceuticals - pharmacokinetics
Rats
Receptors, sigma - metabolism
Stereoisomerism
Structure-Activity Relationship
Tissue Distribution
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Summary:A series of N-(benzofuran-2-ylmethyl)-N′-benzylpiperazines bearing alkyl or fluoroalkyl aryl ethers were synthesized and evaluated at various central nervous system receptors. Examination of in vitro σ1 {[3H](+)-pentazocine} and σ2 ([3H]DTG) receptor binding profiles of piperazines 11−13 and 25−36 revealed several highly potent and σ1 selective ligands, notably, N-(benzofuran-2-ylmethyl)-N′-(4′-methoxybenzyl)piperazine (13, K i = 2.7 nM, σ2/σ1 = 38) and N-(benzofuran-2-ylmethyl)-N′-(4′-(2′′-fluoroethoxy)benzyl)piperazine (30, K i = 2.6 nM, σ2/σ1 = 187). Structural features for optimal σ1 receptor affinity and selectivity over the σ2 receptor were identified. On the basis of its favorable log D value, 13 was selected as a candidate for the development of a σ1 receptor positron emission tomography radiotracer. [11C]13 showed high uptake in the brain and other σ receptor-rich organs of a Papio hamadryas baboon. The in vivo evaluation of [11C]13 indicates that this radiotracer is a suitable candidate for imaging the σ1 receptor in neurodegenerative processes.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm100639f