Huang Y, Hammond P S, Wu L, Mach R H
Department of Radiology, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, USA.
J Med Chem. 2001 Dec 6;44(25):4404-15. doi: 10.1021/jm010384j.
A series of N-(1-benzylpiperidin-4-yl)arylacetamides were synthesized and evaluated for their binding properties for sigma1 and sigma2 receptors. In agreement with previously reported sigma1/sigma2 receptor binding data for N-(1-benzylpiperidin-4-yl)phenylacetamide, all of the N-(1-benzylpiperidin-4-yl)arylacetamide compounds reported below displayed higher affinity for sigma1 vs sigma2 receptors. Replacement of the phenyl ring of the phenylacetamide moiety with a thiophene, naphthyl, or indole aromatic ring had no significant effect on the sigma1 receptor affinity. Replacement of the phenyl ring with an imidazole or pyridyl aromatic ring resulted in a >60-fold loss in affinity for sigma1 receptors and no significant binding affinity for sigma2 receptors. Substitution on the aromatic ring of the benzyl group showed a similar or slightly decreased affinity for sigma1 receptors. Substitution on the aromatic rings of both the phenylacetamide moiety and the benzyl group with a halogen resulted in a similar affinity for sigma(1) receptors and a significantly increased affinity for sigma2 receptors. Comparative molecular field analysis revealed that electrostatic properties of the substituents in the phenylacetamide aromatic ring strongly influenced binding to sigma1 receptors. Compounds 1, 10, 18, 22, 37, and 40 showed the highest selectivity for sigma1 receptors with K(i) (sigma2) to K(i) (sigma(1)) ratios of 100, >92, >122, 77, 74, and 80, respectively. In agreement with previously reported results, the phenylacetamide analogues had no binding affinity for dopamine receptors (D2/D3).
合成了一系列N-(1-苄基哌啶-4-基)芳基乙酰胺，并对其与σ1和σ2受体的结合特性进行了评估。与先前报道的N-(1-苄基哌啶-4-基)苯乙酰胺的σ1/σ2受体结合数据一致，以下报道的所有N-(1-苄基哌啶-4-基)芳基乙酰胺化合物对σ1受体的亲和力均高于σ2受体。用噻吩、萘基或吲哚芳香环取代苯乙酰胺部分的苯环对σ1受体亲和力没有显著影响。用咪唑或吡啶芳香环取代苯环导致对σ1受体的亲和力损失>60倍，对σ2受体没有显著结合亲和力。苄基芳香环上的取代对σ1受体显示出相似或略有降低的亲和力。苯乙酰胺部分和苄基的芳香环上均用卤素取代导致对σ1受体具有相似的亲和力，对σ2受体的亲和力显著增加。比较分子场分析表明，苯乙酰胺芳香环中取代基的静电性质强烈影响与σ1受体的结合。化合物1、10、18、22、37和40对σ1受体表现出最高的选择性，其K(i)(σ2)与K(i)(σ1)的比值分别为100、>92、>122、77、74和80。与先前报道的结果一致，苯乙酰胺类似物对多巴胺受体(D2/D3)没有结合亲和力。
