As an inflammatory mediator histamine plays a pivotal role i

As an inflammatory mediator, histamine plays a pivotal role in nociceptive processes in both the central and peripheral nervous systems (Gemkow et al., 2009; Hough & Rice, 2011; Tiligada et al., 2009). In this respect, the participation of H3Rs in modulating pain, especially neuropathic pain, has attracted attention for the design of H3R-related therapeutic agents, although the function of H3R agonists and antagonists as pain relievers remains a debatable issue and maybe attributable to side-target effects such as sigma-1 receptor antagonism (Berlin et al., 2011; Riddy et al., 2019; Sander et al., 2008; Wijtmans, Leurs, & de Esch, 2007). The available information reveals a paradoxical effect for peripheral and central histamine. Peripheral histamine triggers the stimulation of nociceptive fibers present in the skin and spinal cord, whereas central histamine reduces the transmission of nociception in the brain. There are several reports demonstrating the antinociceptive effect of H3R antagonists originated from augmented release of neuronal histamine (Hough & Rice, 2011). In contrast, inconsistent effects have been observed for H3R agonists (Berlin et al., 2011; Wijtmans et al., 2007). It seems that different animal pain models and administration routes considerably affect the biological response for given H3R agonists/antagonists. But H3R antagonists appear more beneficial in terms of antinociceptive activity and can be promising agents for the treatment of different kinds of pain, in particular neuropathic pain (Berlin et al., 2011; Gemkow et al., 2009). Allergic rhinitis, characterized by inflammation of the nasal membrane, results from an over-activated immune system exposed to trans-isomer in sensitized individuals, and is associated with nasal congestion, rhinorrhea, sneezing, and pruritus. As histamine is a key mediator in triggering allergic rhinitis, preventing the histamine action is a priority in these conditions. Currently, H1 receptor antagonists are extensively utilized for allergic rhinitis; however, in most cases for fully alleviating nasal congestion they are administered alongside α-adrenergic agonists. Since side-effects such as stimulatory CNS and cardiovascular actions have been observed following the administration of α-adrenergic agonists (Berlin et al., 2011; Leurs et al., 2005), designing compounds having fewer side-effects seems beneficial. The function of H3Rs in controlling allergic rhinitis has been widely documented and anti-allergic features of H3R antagonists via noradrenaline release have been reported in several studies (Berlin et al., 2011; McLeod et al., 1999; Repka-Ramirez, 2003; Varty, Gustafson, Laverty, & Hey, 2004). Based on these findings, co-administration of antagonists at H1 and H3 receptors may be a useful alternative to the current pharmacotherapy. On the other hand, the molecular design of hybrid compounds with dual activity on H1 and H3 receptors would be attractive for allergic rhinitis conditions. An inflammatory disease resulting from demyelination and neurodegeneration in CNS is multiple sclerosis (MS), affecting especially young adults and adolescents (Jadidi-Niaragh & Mirshafiey, 2010; Tiligada, Kyriakidis, Chazot, & Passani, 2011). There is evidence indicating that histamine has a regulatory function in experimental allergic encephalomyelitis (EAE), an autoimmune model of MS. Accordingly, targeting H3Rs can be a useful strategy for preventing MS progression (Kremer, Kury, & Dutta, 2015; Schwartzbach et al., 2017). Apart from aforementioned clinical indications discussed above, recent preclinical studies evidenced the effectiveness of H3 antagonists in glaucoma and traumatic brain injury in animal models (Lanzi et al., 2019; Liao et al., 2019). A list of H3R antagonists/inverse agonists currently being investigated in ongoing clinical studies including their clinical status, phase of development, and therapeutic indications along with the corresponding physicochemical and drug-likeness properties is provided in Fig. 3, Tables 1 and 2, and this information is briefly discussed in next section.