Campiani G, Nacci V, Fiorini I, De Filippis M P, Garofalo A, Ciani S M, Greco G, Novellino E, Williams D C, Zisterer D M, Woods M J, Mihai C, Manzoni C, Mennini T
Dipartimento Farmaco Chimico Tecnologico, Università di Siena, Italy.
J Med Chem. 1996 Aug 30;39(18):3435-50. doi: 10.1021/jm960251b.
The "peripheral-type" benzodiazepine receptor (PBR) has been reported to play a role in many biological processes. We have synthesized and tested a novel series of PBR ligands based on a pyrrolobenzoxazepine skeleton, in order to provide new receptor ligands. Several of these new compounds proved to be high affinity and selective ligands for PBR, and benzoxazepines 17f and 17j were found to be the most potent ligands for this receptor to have been identified to date. The SAR and the molecular modeling studies detailed herein delineated a number of structural features required for improving affinity. Some of the ligands were employed as "molecular yardsticks" to probe the spatial dimensions of the lipophilic pockets L1 and L3 in the PBR cleft and to determine the effect of occupation of L1 and L3 with respect to affinity, while other C-7 modified analogues provided information specifically on the hydrogen bonding with a putative receptor site H1. The new pyrrolobenzoxazepines were tested in rat cortex, a tissue expressing high density of mitochondrial PBR, and exhibited IC50 and Ki values in the low nanomolar or subnanomolar range, as measured by the displacement of [3H]PK 11195 binding. A subset of the highest affinity ligands was also found to have high affinities for [3H]PK 11195 and [3H]Ro 5-4864 binding in rat adrenal mitochondria. All the ligands in this subset are stimulators of steroidogenesis having similar potency and extent of stimulation as PK 11195 and Ro 5-4864 of steroidogenesis in the mouse Y-1 adrenocortical cell line.
据报道，“外周型”苯二氮䓬受体（PBR）在许多生物过程中发挥作用。我们基于吡咯并苯并恶唑嗪骨架合成并测试了一系列新型PBR配体，以提供新的受体配体。这些新化合物中有几种被证明是对PBR具有高亲和力和选择性的配体，并且发现苯并恶唑嗪17f和17j是迄今为止已鉴定出的该受体最有效的配体。本文详细描述的构效关系（SAR）和分子模拟研究确定了提高亲和力所需的一些结构特征。一些配体被用作“分子标尺”，以探测PBR裂隙中亲脂性口袋L1和L3的空间尺寸，并确定占据L1和L3对亲和力的影响，而其他C-7修饰的类似物则专门提供了与假定受体位点H1氢键结合的信息。在大鼠皮质（一种表达高密度线粒体PBR的组织）中对新型吡咯并苯并恶唑嗪进行了测试，通过[3H]PK 11195结合的位移测量，其IC50和Ki值处于低纳摩尔或亚纳摩尔范围内。还发现一部分亲和力最高的配体对大鼠肾上腺线粒体中的[3H]PK 11195和[3H]Ro 5-4864结合具有高亲和力。该子集中的所有配体都是类固醇生成的刺激剂，其效力和刺激程度与小鼠Y-1肾上腺皮质细胞系中类固醇生成的PK 11195和Ro 5-4864相似。
