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  • Histamine receptors were largely linked with allergic

    2022-07-02

    Histamine receptors were largely linked with allergic and inflammatory reactions before the recognition of the histamine H3R in 1983 that proved its function as auto- as well as heteroreceptor at pre- and postsynaptic membranes and demonstrated its intense regulating influence on release of numerous central neurotransmitters (Arrang et al., 1988, Arrang et al., 1987, Arrang et al., 1983). Acting as an autoreceptor, H3R inhibits the synthesis and the release of histamine upon its activation. The H3R occurs also as heteroreceptor modulating the release of a number of neurotransmitters including acetylcholine, dopamine, glutamate, noradrenaline and others (Schlicker et al., 1993, Schlicker et al., 1989, Schlicker et al., 1990). Although multipurpose pharmacological tools, localization of H3R and influence on 001 2 functions have been defined in the early years, the development line was shortened for a while. Recovery came from the cloning of the receptor and the discovery of numerous non-imidazole antagonists. Actually, the wide-ranging potential therapeutic indications due to the multiple neurotransmitter balance influenced by H3R promote numerous and heterogeneous possibilities in pharmaceutical industry for innovative blockbusters as well as for pipe-dreams, as an enormous number of potent ligands for the H3R have been described, encompassing significant structural diversity. Accordingly, H3R is a recognized drug target for a wide range of central nervous system (CNS) disorders including cognitive impairment, schizophrenia, sleep/wake disorders (narcolepsy), catalepsy, epilepsy, neuropathic pain, alcohol addiction and energy homeostasis; a small number of selective H3R antagonists have already passed some clinical phase 2 and 3 trials (Berlin and Boyce, 2007, Berlin et al., 2010, Bhowmik et al., 2012, Bonaventure et al., 2007, Brioni et al., 2011, Cowart et al., 2004, Panula et al., 2015, Passani and Blandina, 2011, Stark et al., 2004, Tiligada et al., 2009). Moreover, numerous preclinical studies have revealed the effectiveness of several H3R antagonists in experimental animal models of anxiety and depression, epilepsy, alcohol addiction, and memory impairment (Bahi et al., 2015, Bahi et al., 2013, Bahi et al., 2014, Blandina et al., 1996, Lipani et al., 2014, Sadek et al., 2014a, Sadek et al., 2014b, Sadek et al., 2014c, Sadek et al., 2013b, Tiligada et al., 2009, Walter and Stark, 2012). Importantly, molecular modeling was used to analyze the binding mode and activities of histamine H3 receptor antagonists. A model of the H3R was constructed through homology modeling methods established on the crystal structure of bovine rhodopsin, and known H3R antagonists were interactively docked into the putative antagonist binding pocket (Axe et al., 2006). Consequently, a pharmacophore model was calculated by mapping the features common to three active compounds three-dimensionally in space, and the 3D pharmacophore model complements the atomistic receptor/ligand modeling. Interestingly, the H3R antagonist pharmacophore consists of two protonation sites (basic centers) connected by a central aromatic ring or hydrophobic region. These two basic sites can simultaneously interact with Asp114 in TM3 and a Glu206 in TM5 which are believed to be the key residues that histamine interacts with to stabilize the receptor in the active state (Fig. 2C) (Axe et al., 2006). The interaction with Glu206 is consistent with the enhanced activity resulting from the additional basic site. In addition to these two salt bridging interactions, the central region of these antagonists contains a lipophilic group, usually an aromatic ring that is found to interact with several nearby hydrophobic side chains. Accordingly, the central aromatic feature present in many of the H3R antagonists makes van der Waals contact with several nearby hydrophobic aromatic residue side chains including Tyr115 in TM3 and Trp371 in TM6 (Fig. 2C) (Axe et al., 2006). Also, other three-dimensional atomistic models of antagonist–receptor complexes have successfully been used by applying, e.g. vibrational circular dichroism or density functional theory, to investigate the details of ligand and drug interactions with GPCRs (de Esch et al., 2000, Minick et al., 2007).