Synthesis and in vitro evaluation of tetrahydroisoquinolines with pendent aromatics as sigma-2 (σ2) selective ligands

Abstract

5-Bromo-N-[4-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-butyl)]-2,3-dimethoxybenzamide 1 is a potent and selective σ₂ receptor ligand suitable for further development. A series of new analogues, incorporating a variety of isoquinoline and carboxylic acid moieties, linked together with either a linear or cyclic amine spacer have been synthesised and assessed for their σ₁/σ₂ binding affinity and selectivity. Compounds with a rigid piperidine spacer gave K_i values for the σ₂ receptor between 8.7–845 nM. Changing the configuration of the methoxy groups on the isoquinoline moiety resulted in molecules with σ₂K_i values of 4.4–133 nM whereas varying the length and flexibility of the carbon spaces gave σ₂K_i values 0.88–15.0 nM, some of the most active, selective σ₂ ligands to date. Thus, the flexibility and length of the carbon linker and the carboxylic acid moiety are confirmed to be key to the exceptional binding affinity and selectivity for this active series. Additionally, the incorporation of a halogen on selected carboxylic acid moieties provided a convenient strategy for the introduction of a radiohalogen for applications in pharmacological and imaging studies.