He X S, Bowen W D, Lee K S, Williams W, Weinberger D R, de Costa B R
Laboratory of Medicinal Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892.
J Med Chem. 1993 Mar 5;36(5):566-71. doi: 10.1021/jm00057a006.
2-, 3-, and 4-idophenyl derivatives of the high-affinity sigma ligand N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl)ethylamine (1) were synthesized in two to four steps starting from N-methyl-2-(1-pyrrolidinyl)ethylamine. These compounds were evaluated for their capacity to label both sigma 1 and sigma 2 subtypes in vitro. sigma-1 binding affinity was determined by measuring competition with [3H]-(+)-pentazocine binding to guinea pig brain membranes while sigma 2 binding was evaluated through competition with [3H]DTG binding to rat liver membranes in the presence of excess dextrallorphan. The binding data revealed that N-[2-(3-iodophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl)ethylamine (2) and N-[2-(4-iodophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl)ethylamine (3) displayed almost identical binding affinity at sigma 1 sites to the parent compound 1. This suggests that the 3- or 4-iodo group can effectively substitute for the 3,4-dichloro substituents of 1. In this series of compounds, Ki's at the sigma 1 site varied from 2.0 nM for N-(4-iodobenzyl)-N-methyl-2-(1-pyrrolidinyl)ethylamine (6) to 26.6 nM for N-(2-iodobenzyl)-N-methyl-2-(1-pyrrolidinyl)ethylamine (4). Ki's for sigma 2 site ranged from 8.1 nM for 1 to 220 nM for N-(3-bromobenzyl)-N-methyl-2-(1-pyrrolidinyl)ethylamine (11) while the sigma 2/sigma 1 ratio varied from 1.8 for 4 to 25 for 11. Comparing halogen substitution, the trend Cl = I > Br > F was observed for binding affinity at sigma 1 sites; no such trend was observed at sigma 2 sites. On the basis of the binding data, compounds 2 and 3 were selected for labeling with 123I. Thus, treatment of the corresponding 3- and 4-(tributylstannyl) intermediates (7 and 8) with Na123I in the presence of excess CH3CO3H furnished [123I]-2 and [123I]-3 in up to 70% radiochemical yield. Preliminary in vitro binding with [123I]-3 indicated up to 97% specific binding with guinea pig brain membranes.
以N-甲基-2-(1-吡咯烷基)乙胺为起始原料，经两步至四步反应合成了高亲和力σ配体N-[2-(3,4-二氯苯基)乙基]-N-甲基-2-(1-吡咯烷基)乙胺(1)的2-、3-和4-碘苯基衍生物。对这些化合物在体外标记σ1和σ2亚型的能力进行了评估。通过测量与[3H]-(+)-喷他佐辛与豚鼠脑膜结合的竞争来确定σ-1结合亲和力，而在过量右美沙芬存在下，通过与[3H]DTG与大鼠肝细胞膜结合的竞争来评估σ2结合。结合数据表明，N-[2-(3-碘苯基)乙基]-N-甲基-2-(1-吡咯烷基)乙胺(2)和N-[2-(4-碘苯基)乙基]-N-甲基-2-(1-吡咯烷基)乙胺(3)在σ1位点与母体化合物1表现出几乎相同的结合亲和力。这表明3-或4-碘基团可以有效地取代1的3,4-二氯取代基。在这一系列化合物中，σ1位点的Ki值从N-(4-碘苄基)-N-甲基-2-(1-吡咯烷基)乙胺(6)的2.0 nM到N-(2-碘苄基)-N-甲基-2-(1-吡咯烷基)乙胺(4)的26.6 nM不等。σ2位点的Ki值范围从1的8.1 nM到N-(3-溴苄基)-N-甲基-2-(1-吡咯烷基)乙胺(11)的220 nM，而σ2/σ1比值从4的1.8到11的25不等。比较卤素取代情况，在σ1位点观察到结合亲和力的趋势为Cl = I > Br > F；在σ2位点未观察到这种趋势。根据结合数据，选择化合物2和3用123I进行标记。因此，在过量CH3CO3H存在下，用Na123I处理相应的3-和4-(三丁基锡基)中间体(7和8)，以高达70%的放射化学产率得到[123I]-2和[123I]-3。与[123I]-3的初步体外结合表明，与豚鼠脑膜的特异性结合高达97%。
