新型西格玛受体配体：合成与生物学特性

Novel sigma receptor ligands: synthesis and biological profile.

作者信息

Prezzavento Orazio, Campisi Agata, Ronsisvalle Simone, Li Volti Giovanni, Marrazzo Agostino, Bramanti Vincenzo, Cannavò Giuseppe, Vanella Luca, Cagnotto Alfredo, Mennini Tiziana, Ientile Riccardo, Ronsisvalle Giuseppe

机构信息

Department of Pharmaceutical Sciences, University of Catania, Viale A. Doria 6, 95125 Catania, Italy.

出版信息

J Med Chem. 2007 Mar 8;50(5):951-61. doi: 10.1021/jm0611197. Epub 2007 Feb 13.

DOI:10.1021/jm0611197

PMID:17328523

Abstract

The aim of the present study was to investigate the biological profile of new substituted 1-phenyl-2-cyclopropylmethylamines. High affinity for both sigma subtypes was achieved when 4-phenylpiperidin-4-ol (4a-e) and 4-benzylpiperidine moieties were present (5a-e). (1R,2S/1S,2R)-2-[4-Hydroxy-4-phenylpiperidin-1-yl)methyl]-1-(4-methylphenyl)cyclopropanecarboxylate (4b) showed high affinity for the sigma1 sites (Ki = 1.5 nM) and the most favorable sigma1/sigma2 selectivity (Ki(sigma2)/Ki(sigma1) = 33.9). Binding affinity studies showed that 4b binding on N-methyl-d-aspartate (NMDA), dopaminergic (D1, D2, D3), muscarinic, histaminergic H1, adrenergic (alpha1, alpha2), serotoninergic (5-HT2A, 5-HT2C, 5-HT3, 5-HT4, 5-HT6), DA (DAT), and 5-HT (SERT) transporters was not significant. Interestingly, sigma ligands differently induced the expression of tissue transglutaminase (TG-2) in primary astroglial cell cultures. We suggest that 4b may act as a sigma1/sigma2 agonist and that the sigma ligands may modulate TG-2 differently.

摘要

本研究的目的是调查新型取代的1-苯基-2-环丙基甲胺的生物学特性。当存在4-苯基哌啶-4-醇（4a - e）和4-苄基哌啶部分（5a - e）时，对两种σ亚型均具有高亲和力。(1R,2S/1S,2R)-2-[(4-羟基-4-苯基哌啶-1-基)甲基]-1-(4-甲基苯基)环丙烷羧酸酯（4b）对σ1位点表现出高亲和力（Ki = 1.5 nM）以及最有利的σ1/σ2选择性（Ki(σ2)/Ki(σ1) = 33.9）。结合亲和力研究表明，4b与N-甲基-D-天冬氨酸（NMDA）、多巴胺能（D1、D2、D3）、毒蕈碱、组胺能H1、肾上腺素能（α1、α2）、5-羟色胺能（5-HT2A、5-HT2C、5-HT3、5-HT4、5-HT6）、多巴胺（DAT）和5-羟色胺（SERT）转运体的结合不显著。有趣的是，σ配体在原代星形胶质细胞培养物中对组织转谷氨酰胺酶（TG-2）的表达诱导作用不同。我们认为4b可能作为一种σ1/σ2激动剂，并且σ配体可能对TG-2有不同的调节作用。