de Costa B R, He X S, Dominguez C, Cutts J, Williams W, Bowen W D
Laboratory of Medicinal Chemistry, National Institutes of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Rockville Pike, Bethesda, Maryland 20892.
J Med Chem. 1994 Jan 21;37(2):314-21. doi: 10.1021/jm00028a016.
A series of polyamines based on the high affinity sigma receptor ligand N-[2-(3,4-dichlorophenyl)-ethyl]-N-methyl-2-(1-pyrrolidinyl)ethylamine (3) were developed and evaluated for their binding characteristics at sigma-1 and sigma-2 receptor subtypes. The data indicated that a considerable degree of structural variation is possible while still retaining nanomolar affinity at sigma receptors. As the structure of the polyamines was varied, their binding at sigma-1 and sigma-2 subtypes showed quite different and in some cases opposite trends, supporting the belief that these are pharmacologically distinct entities. Polyamines containing two nitrogen atoms showed optimal binding at both sigma-1 and sigma-2 receptor subtypes. Although additional nitrogen atoms resulted in decreased affinity at sigma-1 and sigma-2 subtypes, an increase in selectivity for sigma-2 subtypes was evident; the parent 3 showed greater selectivity for sigma-1 subtypes. Internitrogen spacings had a large effect on binding affinity and subtype selectivity. For example, the difference between N-[3-(1-pyrrolidinyl)propyl]-N'-(3,4-dichlorobenzyl)-N,N'- dimethylethylenediamine (8) [K(i) = 29.9 nM at sigma-1 receptor and 18.3 nM at sigma-2 receptor] to N-[3-(1-pyrrolidinyl)propyl]-N'-(3,4-dichlorobenzyl)- N,N'-dimethylethylenediamine (10) [K(i) = 1.49 nM at sigma-1 receptor and 12.1 nM at sigma-2 receptor] illustrates the importance of internitrogen spacing. Triamines 11 and 13 [Ki(sigma-2)/K(i)(sigma-1) = 0.19 and 0.10, respectively] containing the N-N-N-Ar spacings 3-3-2 and 4-4-2, proved to be the most sigma-2 subtype selective of the 15 polyamines examined in this study. The N-N-N spacings appear to be an important factor in their sigma-2 subtype selectivity. These compounds will serve as templates in the design of still further sigma-2 subtype selective ligands. The pyrrolidine ring (present in most of the polyamines tested in this series) proved to be an important recognition site for sigma receptor binding activity. Furthermore, alkyl substitution also appears to be important since the stripped down polyamines N-[2-(3,4-dichlorophenyl)ethyl]ethylenediamine (15) and N1-[2-(3,4-dichlorophenyl)ethyl]diethylenetriamine (16) exhibited relatively low binding affinity.
基于高亲和力σ受体配体N-[2-(3,4-二氯苯基)-乙基]-N-甲基-2-(1-吡咯烷基)乙胺(3)开发了一系列多胺，并对其在σ-1和σ-2受体亚型上的结合特性进行了评估。数据表明，在保持对σ受体的纳摩尔亲和力的同时，结构有相当程度的变化是可能的。随着多胺结构的变化，它们在σ-1和σ-2亚型上的结合呈现出截然不同甚至在某些情况下相反的趋势，这支持了它们在药理学上是不同实体的观点。含有两个氮原子的多胺在σ-1和σ-2受体亚型上均表现出最佳结合。虽然额外的氮原子导致在σ-1和σ-2亚型上的亲和力降低，但对σ-2亚型的选择性增加是明显的；母体3对σ-1亚型表现出更大的选择性。氮原子间间距对结合亲和力和亚型选择性有很大影响。例如，N-[3-(1-吡咯烷基)丙基]-N'-(3,4-二氯苄基)-N,N'-二甲基乙二胺(8)[在σ-1受体处K(i)=29.9 nM，在σ-2受体处K(i)=18.3 nM]与N-[3-(1-吡咯烷基)丙基]-N'-(3,4-二氯苄基)-N,N'-二甲基乙二胺(10)[在σ-1受体处K(i)=1.49 nM，在σ-2受体处K(i)=12.1 nM]之间的差异说明了氮原子间间距的重要性。含有N-N-N-Ar间距3-3-2和4-4-2的三胺11和13[Ki(σ-2)/K(i)(σ-1)分别为0.19和0.10]，被证明是本研究中所检测的15种多胺中对σ-2亚型选择性最高的。N-N-N间距似乎是它们对σ-2亚型选择性的一个重要因素。这些化合物将作为进一步设计σ-2亚型选择性配体的模板。吡咯烷环(存在于本系列测试的大多数多胺中)被证明是σ受体结合活性的一个重要识别位点。此外，烷基取代似乎也很重要，因为简化的多胺N-[2-(3,4-二氯苯基)乙基]乙二胺(15)和N1-[2-(3,4-二氯苯基)乙基]二亚乙基三胺(16)表现出相对较低的结合亲和力。
