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  • Multi targeting agents are of major interest in modern drug

    2022-08-01

    Multi-targeting agents are of major interest in modern drug design and discovery. Design of such compounds can be applied to H3R antagonists for the purpose of achieving optimum efficiency as performed for some preclinical candidates such as recently for contilisant (Bautista-Aguilera et al., 2017; Bautista-Aguilera et al., 2018). To this end, different pharmacophores can be combined for developing hybrid and multi-target therapeutic agents useful in the treatment of several diseases with reduced side-effects (Khanfar et al., 2016; Lazewska & Kiec-Kononowicz, 2010; Nikolic et al., 2014; Sander et al., 2008; Stark, 2003; Wijtmans et al., 2007). In context of those poly-pharmacological agents, further research is prompted by recent findings of additional potent sigma 1 receptor binding behavior of some clinically investigated H3R ligands such as ABT-239, S 38093 and PF-3654746 as well as pitolisant (Riddy et al., 2019). Such multi-target directed ligands can be more effective in neurological diseases with multifactorial nature through different embedded pharmacophores required for interactions with multiple targets. Last, but not least, whether or not H3R antagonists/inverse agonists can be used as monotherapy or add-on therapy is a debatable issue, which requires more intensive clinical trial studies containing larger population sizes (Berlin et al., 2011; Celanire et al., 2005; Lazewska & Kiec-Kononowicz, 2010; Tiligada et al., 2009). Overall, in spite of the difficulties faced by the development of H3R antagonists/inverse agonists, there are several drug candidates advanced to different phases of clinical trials and it is expected to witness the marketing of H3R ligands in the near future, in addition to pitolisant (Wakix)®, the only H3R antagonist/inverse agonist approved by the European Medicines Agency and marketed in the European Union for the treatment of narcolepsy.
    Conclusion The BAMB-4 australia H3 receptor has been the focus of a great deal of research over the past four decades and in this context, substantial progress has been made in developing H3R-related ligands. The involvement of H3Rs in many neurological disorders has been documented by several lines of evidence in preclinical studies. In view of this, several non-imidazole based drug candidates as H3R antagonists/inverse agonists are currently undergoing stringent assessments to be entered into the pharmaceutical market. Considering the enormous promise for therapeutic potential of these H3R targeting clinical candidates, it is expected to witness the marketing of these agents as stand-alone or add-on therapy in the near future.
    Conflict of interest
    Acknowledgements This work forms part of the PhD thesis of Nakisa Ghamari at the School of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran. The authors would like to thank the Research Office and Biotechnology Research Center of Tabriz University of Medical Sciences for providing financial support under the Postgraduate Research Grant scheme for the PhD thesis of NG (Grant Number: 57572).
    Introduction Histamine is known to regulate many pathophysiological processes. As examples, histamine has been shown variously to promote allergic inflammation, to induce acid secretion in the gut and to modulate neurotransmission in the central nervous system (Panula et al., 2015). These effects of histamine are mediated by the histamine H1, histamine H2 and histamine H3 receptors, respectively. Historically, the histamine H1 and histamine H2 receptors have served as targets for therapeutically useful drugs, H1 anti-histamines to treat allergic symptoms (Simons and Simons, 1994) and H2 antagonists to counter excess acid secretion (Hershcovici and Fass, 2011). Targeting the histamine H3 receptor has led to the development of selective ligands involved in modifying behavioural disorders (Schwartz, 2011). More recently, a fourth receptor, the histamine H4 receptor, has been identified (Nakamura et al., 2000, Oda et al., 2000). Particular interest in the histamine H4 receptor has developed since a body of emerging data suggests an intimate association of the receptor with diseases that have an allergic basis including atopic dermatitis and asthma (Thurmond et al., 2008) as well as certain auto-immune disorders such as arthritis and multiple sclerosis (Cowden et al., 2013, Liu, 2014, Thurmond, 2015, Kim et al., 2017). Although the histamine H1 receptor has traditionally been associated with allergic reactions, the failure of H1 anti-histamines to provide much symptomatic relief in conditions such as asthma (Simons, 1999) could suggest the participation of an additional or alternative receptor which may involve the histamine H4 receptor (Liu, 2014). Supporting this contention, studies have demonstrated that the histamine H4 receptor can activate a wide variety of pro-inflammatory cells (Thurmond et al., 2008). This has led to the development of histamine H4 receptor antagonists as potential therapeutic agents for diseases with an allergic basis (Thurmond et al., 2008, Walter et al., 2011, Liu, 2014, Thurmond, 2015).