The H R antagonist cimetidine Tagamet became the first

The H2R antagonist cimetidine (Tagamet™) became the first billion-dollar drug in the 1980s for the treatment of peptic ulcer disease. Other H2R antagonists include ranitidine, famotidine, nizatidine, and zolantidine, the latter showing good BBB penetration with a steady-state brain/blood ratio of 1.4 (Young et al., 1988). Despite the widespread use of H2R antagonists for control of gastric ZLN005 release, they are rarely considered as CNS drugs. There are some relevant preclinical research studies highlighting their potential to enhance the effects of opiate analgesics (Nalwalk, Koch, Barke, Bodnar, & Hough, 1995) and for treatment of psychotic disorders (Kaminsky et al., 1990, Mehta and Ram, 2014). H3R has been viewed as a potential pharmacological target for the treatment of cerebral disorders, because it is primarily expressed in the brain (Nuutinen & Panula, 2010). Due to the high constitutive activity of H3R, both the agonists and the antagonists have received much attention. All H3R agonists, including Nα-methylhistamine, (R)-α-methylhistamine, imetit, immepip, methimmepip, proxyfan, and GT-2331, contain the imidazole moiety, which is derived from histamine. Antagonists of H3R are classified into imidazole-based and non-imidazole-based antagonists. Most imidazole-based H3R antagonists, including thioperamide, clobenpropit and ciproxifan, have the disadvantage of poor BBB penetration, interaction with cytochrome P450 proteins, hepatic and ocular toxicities, and incidence of off-target activity at H4R and other receptors (Berlin, Boyce, & Ruiz Mde, 2011). To avoid these problems, non-imidazole-based H3R antagonists, with high affinity and selectivity, have been developed. These include ABT-239, pitolisant, JNJ-5207852, NNC 381049 and GSK189254. H3R antagonists/inverse agonists have been reported to have potential value in the treatment of wake-sleep disorders, cognitive impairment in Alzheimer's disease (AD), and schizophrenia. In March 2016, pitolisant (WakixR) was approved by the European Commission for the treatment of narcolepsy after a decade of intensive studies, which brings new prospects for the development of H3R ligands. However, it is noteworthy that various isoforms of the H3R have been identified in several different species including humans. The long isoform is largely predominant, however, several shorter functional isoforms have been identified including those with deletions in the third intracellular loop (Coge et al., 2001). The autoreceptors that have been shown to modulate histaminergic neurons are short isoforms (Gbahou, Rouleau, & Arrang, 2012). Importantly, H3R isoforms differ markedly in their pharmacological profiles, for example the stereoselectivity of NαMe-αClMeHA enantiomers differs between the short and long isoforms of H3R (Gbahou et al., 2012). It points out the necessity for clarifying the role of H3R in specific cell types and brain regions, in addition to understanding how protein-ligand interactions vary between different H3R isoforms. Many H3 receptor ligands, especially imidazole-containing compounds, also possess significant affinity for the H4R, including (R)-α-methylhistamine, imetit, immepip, and clobenpropit acting as agonists, and thioperamide acting as an inverse agonist of H4R. To date, 4-methylhistamine is the most selective H4R agonist, with >100-fold selectivity over the other histamine receptors (Lim et al., 2005). The indole carboxamide compound, JNJ-7777120, is the first selective and widely used non-imidazole-based H4R antagonist, displaying high selectivity over other histamine receptors (Thurmond et al., 2004). A 2-aminopyrimidine compound, ZPL-3893787 (formerly PF-3893787), has completed phase I studies and is being developed as an oral treatment for atopic dermatitis (Liu, 2014). However, H4R ligands are not currently being evaluated to treat CNS disorders due to the enigmatic role of this receptor in the brain.
The action of histamine and the receptor related ligands in CNS disorders