H3-Receptor antagonists

Histamine produces its pharmacological actions by three subtypes of receptors the postsynaptic Hi and H2 receptors and the presynaptic H3 receptor. The H3 receptor is mainly located in the central nervous system (CNS), where it acts as an inhibitory autoreceptor in the central histaminergic neuronal pathways [176]. A number of therapeutic applications have been proposed for selective H3 receptor antagonists, including several CNS disorders such as Alzheimer s disease. Attention Deficit Hyperactivity Disorder, Schizophrenia, or for enhancing memory or obesity control. 

Histamine decarboxylase knockout mice are unable to produce histamine and these animals are unable to maintain wakefulness in a novel environment. Systemic or intraventricular administration of histamine or Hi receptor agonists induces wakefulness whereas systemic or intraventricular administration of Hi receptor antagonists induces sleep. Local administration of an H3 receptor agonist in the TMN induces sleep whereas local administration of an H3 receptor antagonist into the TMN induces wakefulness. 

The hypothesis of the role of HA in wakefulness stems from the observation that administration of the classical antihistamines (i.e. H3 receptor antagonists) induced sedation. These first-generation antihistamines, used to treat inflammatory reactions, could cross the blood-brain barrier and block the central Hi receptor (White Rumbold, 1988). The first study examining the effect of antihistamines on sleep-wakefulness in cats reported an increase in NREM sleep and a decrease in REM sleep (Jewett, 1968). Similar results were also obtained in dogs (Wauquier et ah, 1981) and humans (Risberg et ah, 1975 Bassano Caille, 1979 Nicholson et ah, 1985 Adam Oswald, 1986). Intraventricular application of HA in the anesthetized rat caused a dose-dependent decrease in the duration of narcosis, whereas intraventricular application of HA in conscious... 

Systemic administration of an H3 receptor antagonist, ciproxifan (1 mg/kg in 0.2 ml, i.m.), induced c-fos expression in the vast majority of HA-immunoreactive... 

Oral administration of the H3 receptor agonist BP 2.94 (20-30 mg/kg) to rats produced a dose-dependent increase in NREM sleep without a significant change in wakefulness or REM sleep. With the highest dose of BP 2.94 (30 mg/kg), the increase in NREM sleep was observed during the second hour and the effect lasted for 6 h. Pretreatment with the H3 receptor antagonist carboperamide (30 mg/kg) prevented the sleep-inducing effects of BP 2.94. In contrast, oral administration of carboperamide (20-30 mg/kg) produced a dose-dependent increase in wakefulness with a concomitant decrease in NREM and REM sleep (Monti et al., 1996). 

In order to explore the importance of the H3 receptor in sleep-wakefulness, Toyota et al. (2002) compared the wake-promoting effects of the H3 receptor antagonist thioperamide in wild-type and H3 receptor KO mice. In wild-type mice, subcutaneous administration of thioperamide (10 mg/kg) increased wakefulness with a concomitant decrease in NREM sleep during the first 2 h after administration at lights-on. REM sleep was unaffected. In contrast, thioperamide had no effect on sleep-wakefulness in H3 receptor KO mice (Toyota et al., 2002). 

Barbier et al. (2004) investigated the effects of a highly selective and novel non-imidazole H3 receptor antagonist, 1, l-[4-(3-piperidin-l-yl-propoxy)-benzyl]-piperidine (JNJ-5207852), on sleep and wakefulness in mice and rats. Systemic injections of JNJ-5207852 (1-10 mg/kg, s.c.) increased the time spent in wakefulness with a concomitant decrease in NREM and REM sleep in both mice and rats. The overall increase in wakefulness was due to an increase in the number of wakefulness bouts. Spectral analysis of the EEG also revealed a reduction in total delta power following systemic injections of this compound (Barbier et ah, 2004). 

Ligneau, X., Lin, J., Vanni-Mercier, G. et at (1998). Neurochemical and behavioral effects of ciproxifan, a potent histamine H3-receptor antagonist. J. Pharmacol. 

Munzar, R, Tanda, G., Justinova, Z., Goldberg, S.R. Histamine h3 receptor antagonists potentiate methamphetamine self-administration and methamphetamine-induced accumbal dopamine release. Neuropsychopharmacology. 29 705, 2004. 

De Esch IJP, Mills JEJ, Perkins TDJ, Romeo G, Hoffmann M, Wieland K, Leurs R, Menge WMPB, Nederkoorn PHJ, Dean PM, Timmerman H. Development of a pharmacophore model for histamine H3 receptor antagonists, using the newly developed molecular modeling program SLATE. J Med Chem 2001 44 1666-1674. 

Witkin JM, Nelson DL. Selective histamine H3 receptor antagonists for treatment of cognitive deficiencies and other disorders of the central nervous system. Pharmacol Ther 2004 103 1-20. 

S. Celanire, M. Wijtmans, P. Talaga, R. Leurs, I.J. de Esch, Keynote review Histamine H3 receptor antagonists reach out for the clinic, Dmg Discov. Today 10(2005) 1613-1627. 

Stark, H. Krause, M. Arrang, J.-M. Ligneau, X. Schwartz, J.-C. Schunack, W. Unsymmetrically Substituted Guanidines as Potent Histamine H3-Receptor Antagonists, Bioorg. Med. Chem. Lett. 1994, 4, 2907-2912. 

In contrast to thioperamide, phenylbutanoylhistamine, an H3-receptor antagonist with moderate potency [51], failed to antagonize the inhibitory effect of (R)a-methylhistamine on acetylcholine release from slices of rat entorhinal cortex [52], In addition, this compound also failed to antagonize the (R)a-methylhistamine-induced inhibition of non-adrenergic non-cholinergic contractions of the guinea pig ileum [53],... 

Schlicker E, Kathmann M, Reidemeister S, Stark H, Schunack W (1994) Novel histamine H3 receptor antagonists affinities in an H3 receptor binding assay and potencies in two functional H3 receptor models. Br J Pharmacol 112 1043-1048 + 113 657 (erratum). 

Stark H, Schlicker E, Schunack W (1996) Developments of histamine H3-receptor antagonists. Drugs Future 21 507-520. 

H3 receptor agonists mimic whereas H3 receptor antagonists block the effect of histamine on 100 mM potassium-evoked release of ACh from the cortex of freely moving rats... 

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