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

详细信息    查看全文

• 作者：Iman A. Moussa ; Samuel D. Banister ; Corinne Beinat ; Nicolas Giboureau ; Aaron J. Reynolds ; Michael Kassiou
• 刊名：Journal of Medicinal Chemistry
• 出版年：2010
• 出版时间：August 26, 2010
• 年：2010
• 卷：53
• 期：16
• 页码：6228-6239
• 全文大小：991K
• 年卷期：v.53,no.16(August 26, 2010)
• ISSN：1520-4804

文摘

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.