Maguire P A, Davies M F, Loew G H
Molecular Research Institute, Palo Alto, CA 94304, USA.
Eur J Pharmacol. 1995 Jul 4;280(2):167-73. doi: 10.1016/0014-2999(95)00199-u.
An alpidem-insensitive benzodiazepine binding site in the rat spinal cord has recently been identified in our laboratory. We report here the binding of 23 1,4-benzodiazepines to this site using [3H]Ro15-4513 (ethyl-8-azido-6-dihydro-5-methyl-4H-imidazo[1,2- a][1,4]benzodiazepine-3-carboxylate) in the presence of 65 microM alpidem (6-chloro-2-(4-chlorophenyl)-N,N- dipropylimidazo[1,2-a]pyridine-3-acetamide). This binding site displays a wide affinity for 1,4-benzodiazepines, most of which show much higher affinity for benzodiazepine receptors in various brain regions and transfected cell systems. The highest affinity ligands are: brotizolam (1-bromo-4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2- f][1,2,4]triazolo[4,3-a][1,4]diazepine) (4.3 nM), Ro15-4513 (5.0 nM), Ro42-8773 (7-chloro-3-[3-(cyclopropylmethoxy)-1-propynyl]-4,5-dihydro- 5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepine-6-one) (5.7 nM), Ro16-6028 (t-butyl (s)-8-bromo-11,12,13,13a-tetrahydro-9-oxo-9H- imidazo[1,5-a][1,4]benzodiazepine-1-carboxylate) (5.9 nM) and triazolam (8-chloro-6-(2-chlorophenyl)-1-methyl-4H- [1,2,4]triazolo[4,3-a][1,4]benzodiazepine) (7.9 nM). The structural feature common to these compounds is an imidazo- or triazolo-ring on the 1- and 2-position of the benzodiazepine. However, the presence of this feature does not guarantee high affinity binding as Ro15-1788 (8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5- a][1,4]benzodiazepine-3-carboxylic acid ethyl ester) (100 nM) and Ro23-0364 (6-[2-chlorophenyl]-4H- imidazo[1,5-a][1,4]benzodiazepine-3-carboxamide) (360 nM) display much lower affinity for this site. Studies are currently underway to investigate the functional significance of this unusual benzodiazepine binding site.
最近我们实验室在大鼠脊髓中发现了一种对阿普地尔不敏感的苯二氮䓬结合位点。在此，我们报告在65微摩尔阿普地尔（6-氯-2-(4-氯苯基)-N,N-二丙基咪唑并[1,2-a]吡啶-3-乙酰胺）存在的情况下，23种1,4-苯二氮䓬与该位点的结合情况，使用的是[3H]Ro15-4513（乙基-8-叠氮基-6-二氢-5-甲基-4H-咪唑并[1,2-a][1,4]苯二氮䓬-3-羧酸酯）。该结合位点对1,4-苯二氮䓬具有广泛的亲和力，其中大多数对不同脑区和转染细胞系统中的苯二氮䓬受体显示出更高的亲和力。亲和力最高的配体有：溴替唑仑（1-溴-4-(2-氯苯基)-9-甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮䓬）（4.3纳摩尔）、Ro15-4513（5.0纳摩尔）、Ro42-8773（7-氯-3-[3-(环丙基甲氧基)-1-丙炔基]-4,5-二氢-5-甲基-6H-咪唑并[1,5-a][1,4]苯二氮䓬-6-酮）（5.7纳摩尔）；Ro16-6028（叔丁基(s)-8-溴-11,12,13,13a-四氢-9-氧代-9H-咪唑并[1,5-a][1,4]苯二氮䓬-1-羧酸酯）（5.9纳摩尔）和三唑仑（8-氯-6-(2-氯苯基)-1-甲基-4H-[1,2,4]三唑并[4,3-a][1,4]苯二氮䓬）（7.9纳摩尔）。这些化合物共有的结构特征是苯二氮䓬的1位和2位上有一个咪唑环或三唑环。然而，具有这一特征并不保证有高亲和力结合，因为Ro15-1788（8-氟-5,6-二氢-5-甲基-6-氧代-4H-咪唑并[1,5-a][1,4]苯二氮䓬-3-羧酸乙酯）（100纳摩尔）和Ro23-0364（6-[2-氯苯基]-4H-咪唑并[1,5-a][1,4]苯二氮䓬-3-甲酰胺）（360纳摩尔）对该位点的亲和力要低得多。目前正在进行研究以探讨这个不同寻常的苯二氮䓬结合位点的功能意义。
