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Histamine H3 Receptor Antagonists/Inverse Agonists

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Histamine H3 Receptor Antagonists/Inverse Agonists Pharmacology & Therapeutics 200 (2019) 69–84 Contents lists available at ScienceDirect Pharmacology & Therapeutics journal homepage: www.elsevier.com/locate/pharmthera Histamine H3 receptor antagonists/inverse agonists: Where do they go? Nakisa Ghamari a,b,OmidZareic,d, José-Antonio Arias-Montaño e, David Reiner f,SiavoushDastmalchia,b, Holger Stark f,⁎, Maryam Hamzeh-Mivehroud a,b,⁎⁎ a Biotechnology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran b School of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran c Cellular and Molecular Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran d Neurosciences Research Center, Kurdistan University of Medical Sciences, Sanandaj, Iran e Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados del IPN, Av. Instituto Politécnico Nacional 2508, Zacatenco, 07360 Ciudad de México, México f Heinrich Heine University Düsseldorf, Institute of Pharmaceutical and Medicinal Chemistry, Universitaetsstr. 1, 40225 Duesseldorf, Germany article info abstract Available online 24 April 2019 Since the discovery of the histamine H3 receptor in 1983, tremendous advances in the pharmacological aspects of H3 receptor antagonists/inverse agonists have been accomplished in preclinical studies. At present, there are sev- Keywords: eral drug candidates that reached clinical trial studies for various indications. However, entrance of these candi- Histamine H3 receptor dates to the pharmaceutical market is not free from challenges, and a variety of difficulties is engaged with their H3 antagonists developmental process. In this review, the potential role of H3 receptors in the pathophysiology of various central H inverse agonists 3 nervous system, metabolic and allergic diseases is discussed. Thereafter, the current status for H receptor antag- Neurological disorders 3 Clinical trials onists/inverse agonists in ongoing clinical trial studies is reviewed and obstacles in developing these agents are Pitolisant emphasized. © 2019 Elsevier Inc. All rights reserved. Contents 1. Introduction............................................... 69 2. H3Rsasatargetfortherapeuticdiscovery................................. 71 3. Clinical trials of current therapeutics targeting H3Rs............................. 73 4. Challenges in the development of H3Rantagonists/inverseagonists...................... 79 5. Conclusion............................................... 80 Conflictofinterest.............................................. 81 Acknowledgements.............................................. 81 References.................................................. 81 1. Introduction Abbreviations: ACh, Acetylcholine; AD, Alzheimer's disease; ADHD, Attention deficit hyperactivity disorder; CIAS, Cognitive impairment associated to schizophrenia; EDS, As an aminergic multifunctional neurotransmitter, histamine [2-(4- γ Excessive daytime sleepiness; GABA, -Aminobutyric acid; H3R, Histamine H3 receptor; 1H-imidazolyl)ethylamine] plays versatile roles in a wide variety of HBA, H-bond acceptor; HBD, H-bond donor; MAPK, Mitogen-activated protein kinase; physiological processes and is therefore also implicated in several path- MLogP, Moriguchi LogP; MS, Multiple sclerosis; MW, Molecular weight; PET, Positron emission tomography; PD, Parkinson's disease. ological conditions (Celanire, Wijtmans, Talaga, Leurs, & de Esch, 2005; ⁎ Corresponding author at: Heinrich Heine University Düsseldorf, Institute of Gemkow et al., 2009; Nikolic, Filipic, Agbaba, & Stark, 2014). Histamine Pharmaceutical and Medicinal Chemistry, Universitaetsstr. 1, 40225 Duesseldorf, is produced in a large number of tissues by cells such as mast cells, Germany. parietal cells of the gastric mucosa, and neurons of central/peripheral ⁎⁎ Corresponding author at: Biotechnology Research Center and School of Pharmacy, nervous system via decarboxylation of L-histidine by histidine decar- Tabriz University of Medical Sciences, Tabriz, Iran. E-mail addresses: [email protected] (H. Stark), [email protected] boxylase (HDC). Histamine inactivation occurs via two major metabolic (M. Hamzeh-Mivehroud). pathways, N-methylation and oxidation. In mammalian brain histamine https://doi.org/10.1016/j.pharmthera.2019.04.007 0163-7258/© 2019 Elsevier Inc. All rights reserved. 70 N. Ghamari et al. / Pharmacology & Therapeutics 200 (2019) 69–84 N-methyltransferase (HNMT) catalyzes the methylation of histamine to (cAMP) with the subsequent reduction in downstream signaling path- τ the H3RinactiveN -methylhistamine, whereas monoamine oxidase and ways such as protein kinase A (PKA) activation and cAMP-responsive aldehyde oxidase are responsible for the formation of (Nτ-methyl)imid- element binding protein (CREB)-induced gene transcription. The Gβγ azole acetic acid by the metabolic oxidation of histamine and to some complexes of Gαi/o proteins inhibit the opening of voltage-activated cal- extent of Nτ-methylhistamine (Berlin, Boyce, & Ruiz Mde, 2011; cium channels, thereby reducing neurotransmitter release (Nieto- Lemke, Williams, & Foye, 2013). Alamilla, Marquez-Gomez, Garcia-Galvez, Morales-Figueroa, & Arias- Histamine exerts its actions through the activation of four distinct re- Montano, 2016). Like other histamine receptors, H3R forms receptor ceptor subtypes (H1 to H4), that belong to the class A family of G protein- heterodimers shown for dopamine D1 and D2 receptors so far (Ferrada coupled receptors (GPCRs) (Leurs, Bakker, Timmerman, & de Esch, 2005; et al., 2008; Vohora & Bhowmik, 2012). Thereby, decreased affinity of Nikolic et al., 2014). Among the histamine receptors, the H3 receptor D2 receptor ligands could be observed in presence of H3Ragonists (H3R) is a pre-synaptically located autoreceptor that inhibits the synthe- in vitro as well as potentiation of D1 and D2 receptor mediated locomo- sis and release of histamine. In addition, H3Rs function as pre-synaptic tor activity by application of the H3R inverse agonist/antagonist heteroreceptors with inhibitory activity on the release of several neuro- thioperamide (Ferrada et al., 2008). Other effector proteins activated transmitters, namely acetylcholine, γ-aminobutyric acid (GABA), dopa- by H3R stimulation include mitogen-activated protein kinases mine, serotonin, noradrenaline and glutamate (Esbenshade et al., 2008). (MAPKs), phosphatidylinositol 3-kinase (PI3K) and phospholipase A2 The H3R was discovered in 1983 by Arrang et al. by analyzing the inhibi- (PLA2) producing arachidonic acid. MAPK and PI3K signaling pathways tion of histamine release in depolarized slices of rat cerebral cortex are associated with the phosphorylation of extracellular signal- (Arrang, Garbarg, & Schwartz, 1983). In 1987, the presence of the recep- regulated kinases (ERKs) and protein kinase B (PKB), respectively, and tor was confirmed by the development of R-α-methylhistamine and the latter inhibits glycogen synthase kinase-3β (GSK-3β). H3R activa- + + thioperamide as selective H3 receptor agonist and antagonist, respec- tion also inhibits the activity of the Na /H exchanger (Bhowmik, tively (Arrang et al., 1987). Later, in 1999 Lovenberg and co-workers Khanam, & Vohora, 2012; Leurs et al., 2005). cloned the gene of the human H3R, which code for a 445 amino acid pro- Fig. 1 illustrates the different signaling pathways elicited or modu- tein (Lovenberg et al., 1999). The H3R is predominantly concentrated in lated by H3R activation. Collectively, the modulation of the release of the central nervous system (CNS); however, it is also expressed periph- histamine and other neurotransmitters through H3R activation could erally in the gastrointestinal tract, the airways, and the cardiovascular be linked to several neurological disorders such as sleep disorders like system (Celanire et al., 2005; Tiligada, Zampeli, Sander, & Stark, 2009). narcolepsy, Alzheimer's disease, attention deficit and hyperactivity dis- The H3R couples to Gαi/o proteins, and hence its stimulation leads to order (ADHD), Parkinson's disease, schizophrenia, multiple sclerosis, inhibition of adenyalate cyclases, diminishing the level of cyclic AMP Tourette's syndrome, pain, obesity etc (Bhowmik et al., 2012; Brioni, Fig. 1. Histamine H3 receptor activation and signaling pathways. Abbreviations: 5-HT: serotonin; AC: adenylyl cyclase; ACh: acetylcholine; Akt: protein kinase B; ALDH: aldehyde dehydrogenase; ATP: adenosine triphosphate; cAMP: adenosine 3′,5′-cyclic monophosphate; DA: dopamine; DAO: Diamine oxidase; GABA: γ-aminobutyric acid; GSK-3β:glycogen synthase kinase-3β;H1R: histamine H1 receptor; H2R: histamine H2 receptor; H3R: histamine H3 receptor; HDC: histidine decarboxylase; HNMT: histamine N-methyltransferase; MAOB: monoamine oxidase B; MAPK: mitogen-activated protein kinase, NA: noradrenaline; NT: neurotransmitter; PI3K: phosphatidylinositol 3-kinase; PKA: protein kinase A; PLA2: phospholipase A2. N. Ghamari et al. / Pharmacology & Therapeutics 200 (2019) 69–84 71 Esbenshade, Garrison, Bitner, & Cowart, 2011; Gemkow et al., 2009; Lin, Parkinson's disease is another neurodegenerative disorder affecting Sergeeva, & Haas, 2011; Passani et al., 2017; Passani & Blandina, 2011; H3Rs. The most common clinical symptoms of this disease are rigidity, Provensi, Blandina, & Passani, 2016; Shan, Bao, & Swaab, 2015). Fig. 2 bradykinesia, rest tremor, loss of postural reflexes, and gain impairment shows the clinical trials reported for H3R antagonists/inverse agonists
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