Efange S M, Mach R H, Smith C R, Khare A B, Foulon C, Akella S K, Childers S R, Parsons S M
Department of Radiology, University of Minnesota, Minneapolis 55455.
Biochem Pharmacol. 1995 Mar 15;49(6):791-7. doi: 10.1016/0006-2952(94)00541-s.
The present study compares the affinities of 2-(4-phenylpiperidino)cyclohexanol (vesamicol, 1) and selected analogues of the latter at the vesamicol receptor (VR) with the corresponding affinities at sigma 1 and sigma 2 binding sites. For this study, the parent structure 1 was divided into three fragments: A (cyclohexyl), B (piperidyl) and C (phenyl). Vesamicol analogues were then selected to reflect structural modifications in these fragments. Consistent with earlier reports, vesamicol was found to exhibit nanomolar affinities at the VR and sigma 1 and sigma 2 sites, resulting in poor selectivity for the VR over the sigma sites. Vesamicol analogues characterized by an acyclic A-fragment showed moderate to low affinities at the VR and moderate to high affinities at sigma 1 and sigma 2 sites. As a result, many of these analogues showed poor selectivity for the VR. Replacement of the C4 carbon of 1 with a halobenzyl amine resulted in higher affinities at the VR coupled with moderate to low affinities at sigma 1 and sigma 2 sites. The introduction of a benzofused substituent at the C4 and C5 positions of 1 (compound 2) resulted in a 200-fold increase in affinity at the VR accompanied by a 5- to 6-fold decrease in affinity at sigma 1 and sigma 2 sites relative to the parent structure. Consequently, compound 2 showed 12,000-fold higher affinity at the VR than at sigma sites. Restricting the rotation of fragment C relative to B (by means of alkyl and alkenyl bridges) generally yielded analogues with subnanomolar affinities at the VR. The corresponding affinities of these spirofused conformationally restricted analogues were moderate to poor at sigma 1 and sigma 2 sites when fragment A was preserved. In contrast, the affinities at sigma 1 and sigma 2 sites were decreased 3- to 11-fold when fragment A was modified at position C4 and decreased up to 100-fold with benzofusion at the C4 and C5 positions of fragment A. Consequently, the spirofused analogues 15-19 were among the most selective VR ligands examined. Thus, the effect of conformational restriction in fragments A and B-C is to increase affinity at the VR while decreasing affinity at sigma 1 and sigma 2 sites, and thereby increasing selectivity for the VR over the sigma sites.
本研究比较了2-(4-苯基哌啶基)环己醇（维生霉素，1）及其选定类似物在维生霉素受体（VR）处的亲和力与它们在σ1和σ2结合位点处的相应亲和力。在本研究中，母体结构1被分为三个片段：A（环己基）、B（哌啶基）和C（苯基）。然后选择维生霉素类似物以反映这些片段中的结构修饰。与早期报告一致，发现维生霉素在VR以及σ1和σ2位点表现出纳摩尔级的亲和力，导致其对VR相对于σ位点的选择性较差。以无环A片段为特征的维生霉素类似物在VR处表现出中等至低亲和力，而在σ1和σ2位点表现出中等至高亲和力。因此，这些类似物中的许多对VR表现出较差的选择性。将1的C4碳用卤代苄胺取代导致在VR处具有更高的亲和力，同时在σ1和σ2位点具有中等至低亲和力。在1的C4和C5位引入苯并稠合取代基（化合物2）导致相对于母体结构，在VR处的亲和力增加200倍，同时在σ1和σ2位点的亲和力降低5至6倍。因此，化合物2在VR处的亲和力比在σ位点高12000倍。相对于B限制片段C的旋转（通过烷基和烯基桥）通常产生在VR处具有亚纳摩尔亲和力的类似物。当保留片段A时，这些螺稠合构象受限类似物在σ1和σ2位点的相应亲和力中等至较差。相反，当片段A在C4位被修饰时，其在σ1和σ2位点的亲和力降低3至11倍，而当片段A的C4和C5位进行苯并稠合时，亲和力降低高达100倍。因此，螺稠合类似物15 - 19是所研究的最具选择性的VR配体之一。因此，片段A和B - C中构象限制的作用是增加在VR处的亲和力，同时降低在σ1和σ2位点的亲和力，从而增加对VR相对于σ位点的选择性。
