H3 histamine

Fig. 9.8 Examples of rule-of-three compliant molecules that have biological activity better than 10 nM. Under each molecule, the following information is included molecule name, MW, ClogP, the biological activity type, value and target. Target names are as follows D3 and D4 - dopaminergic receptor types 2 and 3 AChE and BChE - acetyl- and butyryl-choline esterases PRa and PRb - progesterone receptor types A and B H] and H3, histamine receptor types 1 and 3 5-HT2a, 5-HT2b, 5-HT2c, 5-HT3, 5-HT4 - serotonin receptor subtypes 2A, 2B, 2C, and types 3 and 4 DAT, NET, 5-HTT - dopamine, norepinephrine and serotonin transporter proteins /X], /x.2, S, ki, ks - opioid receptor types mu-1, mu-2, delta, kappa-1 and kappa-3 5a-Rl and 5o -R2 - 5-alpha-reductase isozymes 1 and 2 Flt-1-fms-like tyrosine kinase receptor.

West RE, Zweig A, Shih NY, Siegel MI, Egan RW, Clark MA (1990) Identification of two H3-histamine receptor subtypes. Mol Pharmacol 38 610-613. 

Korte, A., Myers, J., Shih, N.Y., Egan, R.W., Clark, M.A., 1990. Characterization and tissue distribution of H3 histamine receptors in guinea pigs by N -methylhistamine. Biochemical. Biophysical. Res. Comm. 168, 979-986. 

FIGURE 3.11 Inhibition of pH]R -a-methylhistamine ex vivo binding in rat cortex following oral administration of GSK189254 (a H3 histamine receptor antagonist) measured 2h after dosing. Source Redrawn from Medhurst et al... 

Hi and H3 - histamine receptor types 1 and 3,5-HT2A, 5-HT2B, 5-HT20 5-HT3,... 

H3 Histamine-releasing cells Inhibit histamine release ... 

Lead Generation Roved the Way for the Discovery of a Novel H3 Inverse Agonist Clinical Candidate Human H3 histamine receptors... 

Studies have now started to clarify the role of histamine Hi and H2 receptors in the cardiovascular manifestations of anaphylaxis. However, histamine can activate H3 and H4 receptors [56, 57]. Levi and coworkers [58-60] identified H3 receptors as inhibitory heteroreceptors in cardiac adrenergic nerve endings. This suggests a mechanism by which endogenous histamine can activate norepinephrine release in normal and ischemic conditions [61,62]. The functional identification ofH3 receptors in the human heart [59] means that these receptors might be directly and/or indirectly involved in the cardiovascular manifestations of anaphylactic reactions. 

Lovenberg TW, Roland BL, Wilson SJ, Jiang X, Pyati 61 J, Huvar A, Jackson MR> Erlander MG Cloning and functional expression of the human histamine H3 receptor. Mol Pharmacol 1999 55 1101. 

Endou M, Poli E> Levi R Histamine H3 receptor signaling in the heart possible involvement of Gj/Go proteins and N-type Ca channels. J Pharmacol Exp Ther 1994 269 221. bS... 

Imamura M, Seyedi N, Lander HM, Levi R Functional identification of histamine H3-receptors in the human heart. Circ Res 1995 77 206. 

Imamura M, Lander HM, Levi R Activation of histamine H3-receptors inhibits carrier-mediated norepinephrine release during protracted myocardial ischemia. Comparison with adenosine Aj-receptors and a2-adrenoceptors. Circ Res 1996 78 475. 

Silver RB, Mackins CJ, Smith NCE, Koritchneva IL, Lefkowitz K, Lovenberg TW> Levi R Coupling of histamine H3 receptors to neuronal Na+/H+ exchange a novel protective mechanism in myocardial ischemia, Proc Natl Acad Sci USA 2001 98 2855. Silver RB, Poonwasi KS, Seyedi N, Wilson SJ, Lovenberg TW, Levi R Decreased intracellular calcium mediates the histamine H3-receptor-induced attenuation of norepinephrine exocytosis from cardiac sympathetic nerve endings. Proc Natl Acad Sci USA 2002 99 501. 

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. 

Leurs, R, Blandina, P, Tedford, C and Timmerman, H (1998) Therapeutic potential of histamine H3 receptor agonists and antagonists. Trends Pharmacol. Sci. 19 177-183. 

Pollard, H, Moreau, J, Arrang, JM and Schwartz, JC (1993) A detailed autoradiographic mapping of histamine H3 receptors in rat brain areas. Neuroscience 52 168-189. 

Figure 22.7 Histamine influences on sleep and arousal. The activity of histamine-releasing neurons increases with arousal and diminishes during sleep. Both Hi antagonists and agonists of H3-autoreceptors depress release of histamine and reduce arousal (see text for details)...

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. 

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