Huang Y, Hammond P S, Whirrett B R, Kuhner R J, Wu L, Childers S R, Mach R H
Department of Radiology-PET Center, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, USA.
J Med Chem. 1998 Jun 18;41(13):2361-70. doi: 10.1021/jm980032l.
A series of N-(1-benzylpiperidin-4-yl)phenylacetamide derivatives was synthesized and evaluated for affinity at sigma1 and sigma2 receptors. Most of these compounds showed a high affinity for sigma1 receptors and a low to moderate affinity for sigma2 receptors. The unsubstituted compound N-(1-benzylpiperidin-4-yl)phenylacetamide, 1, displayed a high affinity and selectivity for sigma1 receptors (Ki values of 3.90 nM for sigma1 receptors and 240 nM for sigma2 receptors). The influence of substitutions on the phenylacetamide aromatic ring on binding at both the sigma1 and sigma2 receptor has been examined through Hansch-type quantitative structure-activity relationship (QSAR) studies. In general, all 3-substituted compounds, except for the OH group, had a higher affinity for both sigma1 and sigma2 receptors when compared with the corresponding 2- and 4-substituted analogues. The selectivity for sigma1 receptors displayed a trend of 3 > 2 approximately 4 for Cl, Br, F, NO2, and OMe substituted analogues. Halogen substitution on the aromatic ring generally increased the affinity for sigma2 receptors while maintaining a similar affinity for sigma1 receptors. Substitution with electron-donating groups, such as OH, OMe, or NH2, resulted in weak or negligible affinity for sigma2 receptors and a moderate affinity for sigma1 receptors. The 2-fluoro-substituted analogue, 11, exhibited the highest selectivity for sigma1 receptors among all compounds tested, with a Ki value of 3.56 nM for sigma1 receptors and 667 nM for sigma2 receptors. Compounds 1, 5, 9, 11, and 20 had no affinity for dopamine D2 (IC50 > 10 000 nM) and D3 (IC50 > 10 000 nM) receptors. The nanomolar binding affinity and high selectivity for sigma1 receptors suggest that these compounds may be developed as potential radiotracers for positron emission tomography or single photon emission computerized tomography imaging studies.
合成了一系列N-(1-苄基哌啶-4-基)苯乙酰胺衍生物，并对其与σ1和σ2受体的亲和力进行了评估。这些化合物中的大多数对σ1受体表现出高亲和力，对σ2受体表现出低至中等亲和力。未取代的化合物N-(1-苄基哌啶-4-基)苯乙酰胺（1）对σ1受体表现出高亲和力和选择性（σ1受体的Ki值为3.90 nM，σ2受体的Ki值为240 nM）。通过Hansch型定量构效关系（QSAR）研究，考察了苯乙酰胺芳环上取代基对σ1和σ2受体结合的影响。一般来说，与相应的2-和4-取代类似物相比，除了OH基团外，所有3-取代化合物对σ1和σ2受体都具有更高的亲和力。对于Cl、Br、F、NO2和OMe取代的类似物，对σ1受体的选择性呈现出3>2≈4的趋势。芳环上的卤素取代通常会增加对σ2受体的亲和力，同时保持对σ1受体的相似亲和力。用供电子基团（如OH、OMe或NH2）取代会导致对σ2受体的亲和力较弱或可忽略不计，对σ1受体的亲和力中等。在所有测试化合物中，2-氟取代类似物（11）对σ1受体表现出最高的选择性，σ1受体的Ki值为3.56 nM，σ2受体的Ki值为667 nM。化合物1、5、9、11和20对多巴胺D2（IC50>10000 nM）和D3（IC50>10000 nM）受体没有亲和力。纳摩尔级的结合亲和力和对σ1受体的高选择性表明，这些化合物可能被开发为正电子发射断层扫描或单光子发射计算机断层扫描成像研究的潜在放射性示踪剂。
