HA H3 receptor

The HA H3 receptor is further localized on the histaminergic nerve terminals in the brains of rats.40 41-4346 Of the three subclasses of HA receptor that have been identified in the brain, the Hi and H2 receptors are thought to be exclusively post-synaptic.4649 The H3 receptor found on the histaminergic nerve terminal was defined as an autoreceptor and is thus a HA receptor subtype that is uniquely positioned to regulate the amount of HA synthesized and released from the HA neurons.45- 60 Moreover, the presence of H3 receptors on several non-histaminergic nerve terminals (heteroreceptors) has now been further established. Modulation of neurotransmitter... 

Histamine receptors were first divided into two subclasses Hi and H2 by Ash and Schild (1966) on the basis that the then known antihistamines did not inhibit histamine-induced gastric acid secretion. The justification for this subdivision was established some years later when Black (see Black et al. 1972) developed drugs, like cimetidine, that affected only the histamine stimulation of gastric acid secretion and had such a dramatic impact on the treatment of peptic ulcers. A recently developed H2 antagonist zolantidine is the first, however, to show significant brain penetration. A further H3 receptor has now been established. It is predominantly an autoreceptor on histamine nerves but is also found on the terminals of aminergic, cholinergic and peptide neurons. All three receptors are G-protein-coupled but little is known of the intracellular pathway linked to the H3 receptor and unlike Hi and H2 receptors it still remains to be cloned. Activation of Hi receptors stimulates IP3 formation while the H2 receptor is linked to activation of adenylate cyclase. 

The biology of the histamine H3 receptor has been detailed in several recent reviews and will not be discussed in great detail here [1-4]. Rather, we intend to draw attention to the major new biological and medicinal chemistry insights that have emerged in the histamine H3 research community over the last couple of years. 

Although the basic function of the H3 receptor has been known for over two decades, recent years have witnessed a spate of new biological insights, some of which are of particular interest to the medicinal chemist. 

Although most of the medicinal chemistry effort in the H3 receptor field has been focused on the development of antagonists, there is some interest in agonists as well. Histamine H3 receptor agonists decrease the release of histamine in the central and peripheral nervous system and lead to a weakened histaminergic tone. In the brain, their effects will therefore be comparable to those of Hi receptor antagonists, with sedation and induction of sleep as a prominent observation. Indeed, H3 agonists such as the imidazoles... 

Abbott has also demonstrated in vivo efficacy with two piperazine amides, A-304121 (26) and A-317920 (27). Both (26) and (27) bind to the rat H3 receptor with high affinity (pA) = 9.15 and 8.6, respectively) [92] and are active in several in vivo models, including the acute dipsogenia model and models of cognitive performance and inhibitory avoidance [93]. Unfortunately, these compounds showed markedly reduced affinity for the human H3 receptor, reinforcing the need to screen against the human receptor. 

The group at Johnson and Johnson has published several reports on their efforts to find potent H3 antagonists. High-throughput screening using the recombinant human receptor identified the imidazopyridine RWJ-20085 (30) as a weak H3 receptor ligand K — 4 pM). Medicinal chemistry efforts then led to the discovery of the piperidine propyloxy compound (31) [100]. This imidazopyridine has a A) at the human H3 receptor of 2nM and... 

HA receptors are classified into 4 subtypes Hi, H2, H3, and H4 (Hill et al, 1997). All four HA receptor types are metabotropic receptors and belong to the superfamily of G-protein coupled receptors. Ionotropic HA receptors are found in invertebrates (Hardie, 1989 Gisselmann et al., 2002) but are absent from vertebrates (Haas Panula, 2003). Of the four HA receptors, only the Hi, H2, and H3 receptors are found in brain. The recently discovered H4 receptor is predominantly present on leukocytes and may have a critical role in the immune system (Nguyen et al., 2001 Bakker, 2004 Haas 8i Panula, 2003). 

Autoradiographic studies with [3H]R-(a)-methylhistamine have demonstrated the presence of high to moderate levels of H3 receptor binding in almost all layers of the cerebral cortex, striatum, bed nuclei of the stria terminalis, substantia nigra, amygdala, olfactory nucleus, hippocampus, and hypothalamus, especially on the cell somata, dendrites, and axonal varicosities of HA-containing TMN... 

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... 

The H3 receptor functions as an autoreceptor, and its activation leads to a reduction in HA release. Lin and colleagues (1990) studied the effects of H3 receptor ligands on sleep-wakefulness in cats and found that blockade of the H3 receptor by oral administration of thioperamide produced a dose-dependent and long-lasting increase in wakefulness. The highest dose (10 mg/kg) produced a... 

In transfected cells, H3 receptor mediated activation of Gj/0 proteins has also been reported to modulate arachi-donic acid release [29] and the Na+/H+ exchanger [44], and to inhibit Ca2+ influx and exocytosis of [3H] noradrenaline from transfected SH-SY5Y-H3 cells [45], The inhibition of Ca2+ influx may be particularly relevant in view of the known physiological function of the brain H3 receptor. 

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