Novel object recognition test as an alternative approach to assessing the pharmacological profile of sigma-1 receptor ligands

BACKGROUND: Although the terms “agonist” and “antagonist” have been used to classify sigma-1 receptor (σ(1)R) ligands, an unambiguous definition of the functional activity is often hard. In order to determine the pharmacological profile of σ(1)R ligands, the most common method is to assess their potency to alleviate opioid analgesia. It has been well established that σ(1)R agonists reduce opioid analgesic activity, while σ(1)R antagonists have been demonstrated to enhance opioid analgesia in different pain models. METHODS: In the present study, we evaluated the pharmacological profile of selected σ(1)R ligands using a novel object recognition (NOR) test, to see if any differences in cognitive functions between σ(1)R agonists and antagonists could be observed. We used the highly selective PRE-084 and S1RA as reference σ(1)R agonist and antagonist, respectively. Furthermore, compound KSK100 selected from our ligand library was also included in this study. KSK100 was previously characterized as a dual-targeting histamine H(3)/σ(1)R antagonist with antinociceptive and antiallodynic activity in vivo. Donepezil (acetylcholinesterase inhibitor and σ(1)R agonist) was used as a positive control drug. RESULTS: Both tested σ(1)R agonists (donepezil and PRE-084) improved learning in the NOR test, which was not observed with the σ(1)R antagonists S1RA and KSK100. CONCLUSIONS: The nonlinear dose–response effect of PRE-084 in this assay does not justify its use for routine assessment of the functional activity of σ(1)R ligands. GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s43440-023-00516-x.