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  • br Conclusion Our data allow pharmacological discrimination


    Conclusion Our data allow pharmacological discrimination of diverse of H3 ESI-09 antagonists that can be linked to their differential efficacy in preclinical and clinical disease settings (Fig. 6). Moreover, we identify the sigma-1 receptor as a common “off target” for H3 antagonists, and that differential H3 and sigma-1 receptor occupancy may contribute to paradoxical efficacy of compounds such as S3803-2. The work provides an elaborated discovery path for understanding new candidate H3 receptor antagonists.
    Acknowledgements A.C. is a Senior Principal Research Fellow and P.M.S. is a Principal Research Fellow of the National Health and Medical Research Council (NHMRC) of Australia.
    Introduction Organotin compounds (OTs) have been marketed since the 1930s to be used as stabilizers of synthetic polymers such as polyvinyl chloride (Antizar-Ladislao, 2008). It was however the use of trisubstituted organic tin compounds, particularly tributyltin (TBT) and triphenyltin (TPT) as biocides in antifouling paints that contributed very significantly to their large-scale introduction into the environment (Sousa et al., 2014). TBT is extremely toxic towards a wide variety of organisms, from bacteria to mammals, and it was considered the most toxic substance deliberately introduced into the environment (Goldberg, 1986; Sousa et al., 2014). Due to this, the use of TBT was regulated in the European Union through Regulation N782/2003, Decision 2009/425/EC, Regulation N276/2010 and Annex XVII of REACH, 2010. So, TBT use in antifouling paints was banned in 2003 and its use in consumer products was banned in July 2010 (Sousa et al., 2014). Despite being banned, the widespread contamination of marine and freshwater ecosystems, and its ubiquitous occurrence in consumer products, lead to the TBT as a constant presence in our everyday life. Humans are exposed to TBT mainly through the ingestion of contaminated food items (Antizar-Ladislao, 2008; Sousa et al., 2017) and also through the ingestion of house dust, in which levels up to 300 ng/g of TBT have already been reported (Kannan et al., 2010). As a consequence, TBT was recently detected in human blood and serum samples (Antizar-Ladislao, 2008; Kannan et al., 1999; Levine et al., 2015), that may lead to conclude that the human contamination still occurring. This fact may result from TBT bioaccumulation, TBT biomagnification, TBT persistency and/or illegal use of TBT (Antizar-Ladislao, 2008). Moreover, the effect of TBT as an endocrine-disrupter in humans has been postulated by some authors, regarding the disruption in the reproductive and immune systems (Golub and Doherty, 2004; Kannan et al., 1995). Several studies have shown multiple effects of this organotin in various species, such as freshwater planarian (Ofoegbu et al., 2016), bivalves (Hagger et al., 2005; Ruiza et al., 1995), gastropods (Titley-O'Neal et al., 2011), worm (Hagger et al., 2002), ascidian (Ballarin and Cima, 2001), fish (Tian et al., 2015; Zhang et al., 2009), amphibians (Cao et al., 2011) and rats (Cooke et al., 2004). The exposures to TBT significantly reduced locomotion and feeding, delayed head regeneration and DNA damage in planarians (Ofoegbu et al., 2016). In the invertebrates the exposure to TBT induced genotoxic and cytotoxic effects in the early life stages and adult organisms (Grote et al., 2004; Hagger et al., 2005; Hagger et al., 2002; Ruiza et al., 1995). Moreover, one major impact of TBT pollution has been observed for the first time in gastropods, and it is known as “imposex”, the superimposition of male sexual characters onto females (Titley-O'Neal et al., 2011). Regarding vertebrates TBT is able to interfere with the endocrine system as well as the immune system (Hendriksen et al., 2014), the nervous system (Mitra et al., 2013) and cardiovascular system (Nath, 2008). TBT at nM concentrations may exhibit estrogen-like effects, in other works the activation of the classic estrogen receptors induced the same effect as estrogen, on mammalian adipocytes (Penza et al., 2011), and promotes adipogenesis in different animal models (Grun and Blumberg, 2006). It was also demonstrated that TBT inhibited the activity of aromatase, which converts testosterone into estradiol (Omura et al., 2001); and it is able to increase testosterone levels in male rats (Grote et al., 2004).