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  • The measured ROcc values and mg kg respectively

    2021-11-30

    The measured ROcc50 values (4.8 and 42 mg/kg, respectively) were lower than those estimated from the mouse free tak1 inhibitor concentrations (0.4 and 9.3 mg/kg for the sigma-1 and histamine H3 receptor, respectively) or rat CSF levels (0.65 and 4.5 mg/kg, respectively). This discrepancy is almost certainly due to ligand dissociation during the sample preparation for the radioligand binding assay. For example, the measured occupancy of H3 receptors in the rat cortex by the nanomolar affinity antagonist, GSK189254, was approximately 4-fold lower than would be predicted by unbound brain levels (Supplementary Figure A2). It is therefore unsurprising that lower affinity and more rapidly dissociating ligands such as S 38093-2 would be even more prone to discrepancies induced by tissue dilution, despite measures to minimize such effects. Nonetheless, taken together the data suggest that there is likely to be minimal histamine H3 receptor occupancy by S 38093-2 at doses associated with pro-cognitive and anti-hyperalgesic/anti-allodynic activity and that sigma-1 receptor occupancy could contribute to these effects. The sigma-1 receptor is an unusual and poorly understood target, though it is thought to act as an intracellular chaperone (Hayashi et al., 2011) and is implicated in learning and memory, depression, anxiety and schizophrenia (Cobos et al., 2008; Zamanillo et al., 2013). Sigma-1 antagonists are also effective in neuropathic pain (Abadias et al., 2013; Zamanillo et al., 2013) and, whilst the mechanism of action is not well understood, several studies suggest sigma-1 receptors regulate ion channel function (including NMDA/GluN receptors and K+/Ca2+ channels; Cobos et al., 2008). Binding to sigma-1 receptors may also play a role in the pharmacology of the other H3 receptor antagonists examined in this study. Whilst GSK189254 and JNJ-5207852 were highly selective for H3 versus the sigma-1 receptor, ABT-239, PF-2654746 and the approved agent, pitolisant, all displayed similar affinity at both receptors. This is not unprecedented for histamine H3 receptor antagonists: thioperamide and iodophenpropit were both shown to possess sub-micromolar affinity for sigma-1 receptor binding sites (Leurs et al., 1995). As such, sigma-1 affinity should be considered when interpreting the in vivo efficacy of some of these agents. Unfortunately, a lack of canonical functional assays for sigma receptors makes classifying the pharmacology of sigma-targeting ligands challenging – it is possible that differential agonist and antagonist effects could potentially underlie some of the variations in pre-clinical and clinical efficacy with H3 receptor antagonists. Sigma-1 receptor knockout mice or indirect assays, such as regulation of NMDA currents via SK channels in hippocampal slices (Martina et al., 2007) could help understand sigma-1-mediated pharmacology. Interestingly, recent studies have shown that the histamine H3 receptor and the sigma-1 receptor can form heterodimers in both transfected cells and in rodent striatum, and these may play a role in cocaine-seeking (Moreno et al., 2014). Such an interaction provides a potential physical mechanism by which the properties of S 38093-2 (herein and elsewhere; Panayi et al., 2017) may be reconciled. Recently an X-ray crystal structure of the sigma-1 receptor was solved, revealing it to be a single transmembrane domain protein (Schmidt et al., 2016); hopefully this will lead to further understanding of the function of this enigmatic protein family and the drugs that target it. In summary we demonstrate that S 38093-2 preferentially occupies sigma-1 receptors at pro-cognitive and anti-hyperalgesic/anti-allodynic doses, whilst occupying the histamine H3 receptor at doses associated with wakefulness and neurotransmitter release. These findings help explain the in vivo pharmacology of S 38093-2 and aid in the differentiation of histamine H3 receptor antagonists, which in turn could contribute to some of their pre-clinical or clinical efficacy.