Methyl substitution on the piperidine ring of N-[ω-(6-methoxynaphthalen-1-yl)alkyl] derivatives as a probe for selective binding and activity at the σ1 receptor
Methyl substitution on the piperidine ring of N-[ω-(6-methoxynaphthalen-1-yl)alkyl] derivatives as a probe for selective binding and activity at the σ1 receptor
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DOI：
10.1021/jm050654o
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发表时间：
2005-12-29
影响因子：
7.3
通讯作者：
Perrone, R
中科院分区：
文献类型：
--
作者：
Berardi, F;Ferorelli, S;Perrone, R
合成了不同甲基哌啶类化合物的N-(6-methoxy-1，2，3，4-tetrahydronaphthalen-1-yl)propyl和N-(6-甲氧基萘-1-基)丙基及其上同系丁基衍生物。以含有单甲基或双甲基的哌啶部分为探针，通过Sigma(1)和Sigma(2)受体以及Delta(8)-Delta(7)甾醇异构酶(SI)位点的放射配基结合分析，探索a亚型的亲和力和选择性。4-甲基衍生物31是最有效的sigma(1)配体(K-I=0.030 nM)，具有良好的选择性(分别是sigma(2)受体和SI位点的597倍和268倍)，而3，3-二甲基衍生物26(K-I=0.35 nM)是相对于sigma(2)受体选择性最高的(680倍)。这两种化合物都可以作为PET实验的工具。此外，化合物26、28、31和33在大鼠C6胶质瘤细胞中表现出抗增殖活性(EC50=15.0mU/33)，显示出潜在的α-受体拮抗剂活性，为肿瘤的研究和治疗开辟了广阔的前景。
The N-(6-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl and N-(6-methoxynaphthalen-1-yl)propyl derivatives as well as their upper homologous butyl derivatives of various methyl-piperidines were prepared. The piperidine moiety bearing monomethyl or geminal dimethyl groups was employed as a probe to explore a-subtype affinities and selectivities by radioligand binding assays at sigma(1) and sigma(2) receptors and the Delta(8)-Delta(7) sterol isomerase (SI) site. 4-Methyl derivative 31 was the most potent sigma(1) ligand (K-i = 0.030 nM) with a good selectivity profile (597-fold and 268-fold relative to sigma(2) receptor and SI site, respectively), whereas 3,3-dimethyl derivative 26 (K-i = 0.35 nM) was the most selective (680-fold) relative to the sigma(2) receptor. Both compounds can be proposed as tools for PET experiments. Furthermore, the naphthalene compounds 26, 28, 31, and 33 demonstrated antiproliferative activity in rat C6 glioma cells (EC50 = 15.0 mu M for 33), revealing a putative a, antagonist activity and opening a useful perspective in tumor research and therapy.