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Pitolisant and Other Histamine-3 Receptor Antagonists—An Update on Therapeutic Potentials and Clinical Prospects

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Pitolisant and Other Histamine-3 Receptor Antagonists—An Update on Therapeutic Potentials and Clinical Prospects medicines Review Pitolisant and Other Histamine-3 Receptor Antagonists—An Update on Therapeutic Potentials and Clinical Prospects Victoria Harwell and Pius S. Fasinu * Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Campbell University, Buies Creek, NC 27501, USA; [email protected] * Correspondence: [email protected] Received: 28 July 2020; Accepted: 27 August 2020; Published: 1 September 2020 Abstract: Background: Besides its well-known role as a peripheral chemical mediator of immune, vascular, and cellular responses, histamine plays major roles in the central nervous system, particularly in the mediation of arousal and cognition-enhancement. These central effects are mediated by the histamine-3 auto receptors, the modulation of which is thought to be beneficial for the treatment of disorders that impair cognition or manifest with excessive daytime sleepiness. Methods: A database search of PubMed, Google Scholar, and clinicaltrials.gov was performed in June 2020. Full-text articles were screened and reviewed to provide an update on pitolisant and other histamine-3 receptor antagonists. Results: A new class of drugs—histamine-3 receptor antagonists—has emerged with the approval of pitolisant for the treatment of narcolepsy with or without cataplexy. At the recommended dose, pitolisant is well tolerated and effective. It has also been evaluated for potential therapeutic benefit in Parkinson disease, epilepsy, attention deficit hyperactivity disorder, Alzheimer’s disease, and dementia. Limited studies have shown pitolisant to lack abuse potential which will be a major advantage over existing drug options for narcolepsy. Several histamine-3 receptor antagonists are currently in development for a variety of clinical indications. Conclusions: Although limited clinical studies have been conducted on this new class of drugs, the reviewed literature showed promising results for future additions to the clinical indications of pitolisant, and the expansion of the list of approved drugs in this class for a variety of indications. Keywords: cataplexy; excessive daytime sleep; histamine-3 receptor antagonists; narcolepsy; pitolisant; sleep 1. Introduction Histamine (2-(imidazol-4-yl) ethylamine), an endogenous monoamine, is one of the most studied chemical mediators in the biological systems involved in various physiological and pathological processes including cell proliferation and differentiation, tissues regeneration, wound healing, and immunomodulation [1–3]. First synthesized in 1907 and characterized in 1910, histamine and its roles in mediating anaphylactic reactions and body secretions have been explored for the development of a wide range of drugs referred to as antihistamines whose pharmacological effects are receptor-dependent. Earlier studies of the distribution and functions of histamine receptors led to the differentiation of histamine-1 (H1R) and histamine-2 (H2R) receptors in 1966 [4,5]. The histamine-3 receptor (H3R), discovered in 1983, was determined to be a presynaptic autoreceptor that inhibits histamine release in the brain [6]. A 445-amino-acids G-protein-coupled receptor, highly selective and specific for histamine, H3R has been described as a heteroreceptor for regulating the release of other neurotransmitters. Highly expressed in the basal ganglia, globus pallidus, hippocampus, and cortex of Medicines 2020, 7, 55; doi:10.3390/medicines7090055 www.mdpi.com/journal/medicines Medicines 2020, 7, x FOR PEER REVIEW 2 of 19 release of other neurotransmitters. Highly expressed in the basal ganglia, globus pallidus, hippocampus, and cortex of the CNS, the H3Rs play important roles in cognition compared to the Medicines 2020, 7, 55 2 of 16 H1R and H2R whose roles are mostly peripheral [7]. H3R activation is associated with arousal, cognition, fluid, food and temperature homeostasis, cardiovascularthe CNS, the H3Rs control, play anxiety, important and roles pain in cognitionperception. compared When activated, to the H1R H3R and causes H2R whoseGαi/o- rolesprotein are- coupledmostly peripheral inhibition [ 7of]. adenylate cyclase and the Na+/H+ exchange. It also stimulates the GTPγS binding,H3R phospholipase activation is A2 associated mitogen-activated with arousal, protein kinase, cognition, and GSK fluid,-3β and food AKT. and The temperature stimulation ofhomeostasis, the H3R receptor cardiovascular can impair control, cognition anxiety, and many and pain of th perception.e signaling pathways When activated, it is associated H3R causes with areGα iconnected/o-protein-coupled to long-term inhibition plasticity, of adenylate neuronal cyclase cell death, and and the Naneuronal+/H+ exchange. migration/neuroprotection It also stimulates [8].the The GTP γeffectS binding, of H3R phospholipase agonism includes A2 mitogen-activatedthe inhibition of neurotransmitter protein kinase, andrelease GSK-3 withβ andpotential AKT. benefitsThe stimulation in allergic of therhinitis, H3R cardiac receptor dysfunction, can impair cognitionand ventricular and many arrhythmias, of the signaling all of which pathways are triggeredit is associated by excessive with norepinephrine are connected tolevels long-term (Figure plasticity,1). Antagonism neuronal of the cell H3R death, enhances and the neuronal release ofmigration the neurotransmitters/neuroprotection [histamine,8]. The eff ectacetylcholine, of H3R agonism dopamine, includes norepinephrine, the inhibition of neurotransmitterand others. An enhancedrelease with release potential of histamine benefits incan allergic be beneficial rhinitis, in cardiac the therapeutic dysfunction, management and ventricular of disease arrhythmias, conditions all associatedof which are with triggered exces bysive excessive daytime norepinephrine sleepiness (EDS) levels (Figuresuch 1as). Antagonismnarcolepsy, ofparkinsonism, the H3R enhances and obstructivethe release ofsleep the neurotransmittersapnea (OSA). Enhanced histamine, histamine acetylcholine, release dopamine,is also known norepinephrine, to enhance andcognition, others. Anwhich enhanced is considered release of beneficial histamine in can such be beneficial disease instates the therapeutic as attention management deficit hyperactivity of disease conditions disorder (ADHD),associated Alzheimer’s with excessive disease, daytime and sleepiness schizophrenia. (EDS) suchThe asmechanism narcolepsy, behind parkinsonism, the potential and obstructive benefit in ADHDsleep apnea includes (OSA). the Enhanced blockade histamineof decreasing release impulsivity, is also known improving to enhance attention, cognition, and enhancing which is considered learning andbeneficial memory in such [9]. The disease mechanism states as behind attention the deficit potential hyperactivity therapeut disorderic use in (ADHD),Alzheimer’s Alzheimer’s disease includes disease, theand reported schizophrenia. increase The of mechanismhistamine in behind the frontal thepotential cortex and benefit hippocampus in ADHD but includes there are the also blockade reports of ofdecreasing decreased impulsivity, histamine in improving the hippocampus attention, and and other enhancing areas learningof the brain. and H3R memory antagonism [9]. The is mechanism theorized tobehind improve the potentialrecognition therapeutic memory, use spatial in Alzheimer’s memory, memory disease includesconsolidation, the reported and working increase memory of histamine [10– 1in2]. the frontal cortex and hippocampus but there are also reports of decreased histamine in the hippocampusThe aim of and the other current areas review of the is brain.to provide H3R an antagonism update on isH3R theorized receptor to antagonists improve recognition including pitolisant,memory, spatial which memory,have been memory approved consolidation, for clinical use, and workingand others memory in development. [10–12]. Figure 1. 1. ReleasedReleased histamine histamine (represented (represented by the by blue the dots) blue dots)from the from histaminergic the histaminergic neurons neuronsbind to histaminebind to histamine-1-1 and -2 andreceptors -2 receptors on the oneffector the eff ectorneurons, neurons, while whilesome someare metabolized are metabolized to the to theN- methylhistamineN-methylhistamine by bythe the histamine histamine NN-methyltransferase-methyltransferase (HNMT) (HNMT) enzyme. enzyme. Some Some of of the the released histamine binds to the histamine histamine-3-3 autoreceptors (on the histaminergic neurons) and the histamine histamine-3-3 heteroreceptors (on the non non-histaminergic-histaminergic neurons) thereby inhibiting the reuptake of released neurotransmitters. The The central central effect effect o off this this inhibition inhibition includes includes the the enhancement of of wakefulness, cognition, learning learning,, and memory [13].]. The aim of the current review is to provide an update on H3R receptor antagonists including pitolisant, which have been approved for clinical use, and others in development. Medicines 2020, 7, 55 3 of 16 Medicines 2020, 7, x FOR PEER REVIEW 3 of 19 2. Methods 2. Methods A literature search was completed in June 2020 on the PubMed database, Google Scholar, A literature search was completed in June 2020 on the PubMed database, Google Scholar, and and clinicaltrials.gov. There were no time restrictions implemented on when articles were published. clinicaltrials.gov. There were no time restrictions implemented on when articles were published. The The search strategy was constructed to find relevant articles addressing the therapeutic
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