Synthesis of novel (benzimidazolyl)isoquinolinols and evaluation as adenosine A1 receptor tools

Abstract

G protein-coupled receptors (GPCRs) constitute the largest family of transmembrane receptors in eukaryotes. The adenosine A1 receptor (A1AR) is a class A GPCR that is of interest as a therapeutic target particularly in the treatment of cardiovascular disease and neuropathic pain. Increased knowledge of the role A1AR plays in mediating these pathophysiological processes will help realise the therapeutic potential of this receptor. There is a lack of enabling tools such as selective fluorescent probes to study A1AR, therefore we designed a series of (benzimidazolyl)isoquinolinols conjugated to a fluorescent dye (31-35, 42-43). An improved procedure for the synthesis of isoquinolinols from tetrahydroisoquinolinols via oxidation with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and atmospheric oxygen is reported. This synthetic method offers advantages over previous metal-based methods for the preparation of isoquinolinols and isoquinolines, which are important scaffolds found in many biologically active compounds and natural products. We report the first synthesis of the (benzimidazolyl)isoquinolinol compound class, however the fluorescent conjugates were not successful as A1AR fluorescent ligands.