The H autoreceptors distributed mainly

The H3 autoreceptors distributed mainly in the CNS act as a negative feedback on histamine synthesis and release from histaminergic neurons. Histamine is involved in many physiological functions such as sleep-wake regulation, circadian and feeding rhythm, thermal regulation, locomotion, learning, cognition, and memory (Berlin et al., 2011; Nikolic et al., 2014; Passani & Blandina, 2011; Sadek, Saad, Sadeq, et al., 2016; Tiligada et al., 2011). The expression of H3Rs is not limited to histaminergic neurons but they function as also as heteroreceptors on aminergic neurons (e.g. those releasing acetylcholine, dopamine, noradrenaline, and serotonin), as well as on glutamatergic, GABAergic and peptidergic neurons, located in different regions of the Rizatriptan Benzoate such as cerebral cortex, hippocampus, nucleus accumbens, nucleus basalis magnocellularis, and basal ganglia (Haas, Sergeeva, & Selbach, 2008; Nieto-Alamilla et al., 2016; Schlicker & Kathmann, 2017). The blockade of pre-synaptic H3 autoreceptors leads to the removal of the negative feedback with the subsequent increase in the levels of histamine and other neurotransmitters. In the past decades, H3Rs have raised widespread attention in both academia and pharmaceutical companies due to their involvement in the pathophysiology of several diseases, especially neurological disorders. There are numerous ongoing projects in which H3Rs are considered as potential drug targets for a variety of neurodegenerative disorders (e.g. sleep disorders, Alzheimer's disease, schizophrenia, ADHD, and MS), metabolic syndrome (obesity), nasal inflammatory diseases (e.g. allergic rhinitis and congestion), and pain. In view of this, several attempts have focused on H3R antagonists/inverse agonists for the purpose of developing novel therapeutic agents. Initially, medicinal chemistry efforts resulted in the development of imidazole-based H3R antagonists by the structural increase of histamine in terms of bulkiness assuming that the imidazole heterocycle ring is critical for receptor binding. However, imidazole-based compounds were not successful due to drawbacks observed in several investigations. Binding discrepancies among species, low CNS penetration, rapid metabolism (HMT substrates), off-target activity, liver toxicity and, more importantly, high potential for cytochrome P450 inhibition are the reasons for excluding these agents from the therapeutic area (Berlin et al., 2011; Brioni et al., 2011; Esbenshade, Fox, & Cowart, 2006; Khanfar et al., 2016; Kuhne, Wijtmans, Lim, Leurs, & de Esch, 2011; Lazewska & Kiec-Kononowicz, 2010; Nieto-Alamilla et al., 2016; Nikolic et al., 2014; Plancher, 2011; Sadek & Stark, 2016; Sander et al., 2008; Schlicker & Kathmann, 2017; Stark, 2003; Wijtmans et al., 2007). In the continued efforts, the hurdles were relatively overcome by a new generation of H3R antagonists/inverse agonists lacking the imidazole ring. Since this ring is capable of establishing hydrogen bonds, CNS penetration and oral bioavailability would be low for imidazole-based compounds (Sander et al., 2008). These are the driving forces for the development of non-imidazole agents through biosterically replacing imidazole with N-containing non-aromatic heterocycles such as piperidine, pyrrolidine, piperazine, and azepane. Historically, introducing non-imidazole based compounds was a milestone in the field of H3R research as they are highly selective and potent with improved pharmacokinetic properties (Berlin et al., 2011; Esbenshade et al., 2006; Nieto-Alamilla et al., 2016; Nikolic et al., 2014; Schlicker & Kathmann, 2017). The induction of hippocampal neurogenesis by H3R antagonists/inverse agonists evidenced by a study in mice can be regarded as an advantage of these agents for reversing age-associated cognitive deficits (Guilloux et al., 2017). In addition, the lower expression of H3Rs in peripheral tissues compared to the CNS is a benefit for antagonists/inverse agonists having limited non-CNS side-effects (Esbenshade et al., 2008). However, it is worth mentioning that lipophilicity and polar surface area are the crucial parameters to be optimized for designing therapeutic agents targeting peripheral H3Rs (Kuhne et al., 2011).