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  • br Histamine H R Many of

    2021-09-16


    Histamine H3R Many of the highlight H3R ligands have been described as suitable pharmacological tools for in vitro or in vivo studies and are designated here. The number of ligands and structural categories is huge, and a number of inclusive reviews of the SAR and properties of H3R ligands have been published (Amon et al., 2007, Berlin and Boyce, 2007, Berlin et al., 2010, Berlin et al., 2011, Celanire et al., 2005, Esbenshade et al., 2008, Gemkow et al., 2009, Lazewska and Kiec-Kononowicz, 2010, Panula et al., 2015, Sander et al., 2008, Tiligada et al., 2009).
    H3R agonists At H3Rs, histamine (1) itself is a highly active agonist. Potent H3R agonists have been achieved by simple structural modifications of the histamine molecule. The methylated analog 3H-Nα-methylhistamine (NAMH, 30) (Arrang et al., 1987) is not selective for H3R (vs H1R, H2R), but has found a wide use in radioligand TC-I 15 binding assays due to its high affinity at rat H3Rs (Arrang et al., 1983, Hill et al., 1997) and ready availability in tritiated form. R-(α)-methylhistamine (28) is highly potent (Arrang et al., 1985a, Arrang et al., 1985b, Hill et al., 1997) and is also used as an in vitro agonist tool (Fig. 5). Also, R-(α)-methylhistamine does have significant H4R activity (Liu et al., 2001, Morse et al., 2001, Panula et al., 2015). This agonist also induces dipsogenic effect in numerous animal experiments, a finding used as the source of an in vivo pharmacological model (Clapham and Kilpatrick, 1993, Fox et al., 2002, Ligneau et al., 1998). Interestingly, prodrugs of R-(α)-methylhistamine have been described with an improved pharmacokinetic profile, e.g. BP2-94 (29) (Krause et al., 2001, Stark et al., 2001). In addition, more potent agonists were developed later; replacing the amine group in histamine by an isothiourea moiety (imetit, 31) or elongating and cyclizing the side chain (immepip, TC-I 15 32) with improved lipophilicity (Arrang et al., 1987, Coruzzi et al., 1995, Garbarg et al., 1992, Nikolic et al., 2014, Panula et al., 2015, Vollinga et al., 1992). However, all three compounds were, also, found to be dual-acting H3R/H4R agonists. Interestingly, the fluctuating change from agonist to antagonist behavior is more complex with histamine H3Rs than with any other of the HR subtypes. Consequently, inverse agonists can be found due to high constitutive activity of H3Rs as well as neutral antagonists (Morisset et al., 2000, Panula et al., 2015, Schwartz et al., 2003, Tiligada et al., 2009). Based on theoretical aspects of receptor theory, ligands with protean agonist properties have been labeled displaying the whole spectra of pharmacological responses from inverse agonist to neutral antagonist to (partial) agonist in one molecule depending on the test system. Proxyfan (33) was the first compound as protean agonist for H3Rs (Kenakin, 2001, Tiligada et al., 2009). Different degrees of partial (ant)agonist properties were later also found in other series of non-amine imidazole derivatives like GT-2331 (ciprilisant, 34) (Fig. 5) (Ito et al., 2006, Liu et al., 2004, Panula et al., 2015, Tedford et al., 1999, Tiligada et al., 2009).
    H3R antagonists Notably, H4R was found to show a 35% amino acid homology with the H3R and much lower homologies to H1Rs and H2Rs (Liu et al., 2001, Morse et al., 2001, Nakamura et al., 2000, Nguyen et al., 2001, Oda et al., 2000, Zhu et al., 2001). Therefore, the latter observation is reflected in the pharmacological profile of known HR ligands, where most H1R and H2R antagonists and agonists do not bind at the H4R (Jablonowski et al., 2004, Jablonowski et al., 2003). Also, a very recent preclinical study in experimental models of seizures and memory showed that the H3R antagonist DL77 exhibits anticonvulsant effects and improves cognitive performance through actions on different memory stages, demonstrating that H3Rs may have implications for the treatment of degenerative disorders associated with impaired memory function and may represent a novel therapeutic pharmacologicaltarget to tackle cognitive problems associated with the chronic use of antiepileptic drugs (Sadek et al., 2015, Neuropharmacology, pages 1-10). However, some of the H3R ligands (like R-α-methylhistamine, thioperamide, and imetit) do bind to the H4R, albeit with affinities different from that of the H3R (Hofstra et al., 2003, Jablonowski et al., 2003).