Histamine H3-Receptor Ligands

Potent Hi agoni.sts (Fig. 21-18) arc obtained by simple modifications of the histamine molecule. The imida/olc ring is a common. structural feature in almost all Hi agonists. Methylation of the aminocthyl side chain of histamine favors 

The hetcrocyclc component of this general structure is most commonly a 4-monosubstituted imida/.ole or bioisast-cric equivalent. Chains A and B can be of various structures and lengths, and there is al.so wide latitude in the structural icquircmcnls for the polar group. Halogenated phenyl, cycloalkyl, and heteroaryl structures are usually found for ihc lipophilic moiety (Hig. 21-19). 

4 Cosy. A. F. The Slcric Factor in Medicinal Chcniisiry Dissymmetric Piu s of Phanii c d(Fgical Receptors. New Y irk. Plemini lYess. 199.. Chap II. 

Witiak. D. T. Antiallergeiiic agents. In Burger. A. (cd.). Medicinal Chemistry.. 4nled. New York. Wiley Interscicncc. 1970. p. U 43. 

Receptors for histamine. In Schaehtcr. M. (ed ). Histamine and Antihistatnines. New York. Pergamon Press. 1973. p. 3. 

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Vanni-Mercier, G Gigout, S., Debilly, G. Lin, J. S. (2003). Waking selective neurons in the posterior hypothalamus and their response to histamine H3-receptor ligands an electrophysiological study in freely moving cats. Behav. Brain. Res. 

Yates, S. L., Phillips, J. G., Gregory, R. etal. Identification and pharmacological characterization of a series of new 1H-4-substituted-imidazoyl histamine H3 receptor ligands. J. Pharmacol. Exp. Ther. 289 1151-1159,1999. 

It is evident, therefore, that the role of histamine H3-receptors in the control of rat cardiac function is still an open question, since results were obtained in different in vitro and in vivo conditions and were related to the methods employed (see Table 7), as well as perhaps to the side effects of some histamine H3 receptor ligands. 

THERAPEUTIC POTENTIAL OF HISTAMINE H3 RECEPTOR LIGANDS IN PERIPHERAL TISSUES... 

So far no H3 ligand have been introduced into therapy, and we have to wait for results of clinical trials, which are in progress with the prodrug BP 2-94 (Rouleau et al., 1997), before the potential therapeutic usefulness of histamine H3 receptor ligands in peripheral diseases can be definitely assessed. 

Molecular modelling studies of histamine H3 receptor ligands... 

Bailey JM, Bruton G, Huxley A, Milner PH, Orlek BS (2005) Substituted piperidines as histamine H3 receptor ligands. W02005/14571... 

Arrang, J. M., Garbarg, M., Lancelot, J. C. et al. (1987a). Highly potent and selective ligands for histamine H3-receptors. Nature 327, 117-23. 

Lim HD, van Rijn RM, Ling P, Bakker RA, Thurmond RL, Leurs R. Evaluation of histamine HI-, H2-, and H3-receptor ligands at the human histamine H4 receptor identification of 4-methylhistamine as the first potent and selective H4 receptor agonist. J Pharmacol Exp Ther 2005 314 1310-21. 

Histamine H3 receptor stimulation is not involved in the direct effects of histamine in the permeability response in in vivo rats, (Pile and Smaje., 1992) In this last study, Hi and H2 receptors seem to have a dominant role. However, the H3-receptor antagonist thioperamide prevents the effects induced by histamine and by the Hi-agonist 2-thiazolylethylamine, thus suggesting non-specific interactions of these histamine receptor ligands... 

Regarding human tissues, the few data available are contradictory, since according to some authors (Tedeschi et al., 1991) histamine release from basophils is not modified by H3 receptor ligands. In other studies (Bent et al., 1991), it was found that thioperamide could increase histamine release from adenoidal mast cells, but apparently (R)a-methylhistamine was totally inactive. In any case the concentrations of thioperamide are much higher than those necessary to block H3 receptors, thus suggesting that other mechanisms might be involved. Raible et al., (1994) hypothesized by the use of thioperamide, the presence of H3 receptors on human eosinophils which mediate histamine-induced increase in cytosolic calcium mobilization. However, the low efficacy of the known H3 receptor agonists, -as stimuli for eosinophils... 

Histamine H3 receptors are well distributed in peripheral tissues, although relatively less abundant than in the CNS. As for the cellular localization, peripheral H3 receptors are present in different cell types, like the neural, paracrine, endocrine, muscular and endothelial cells, where they subserve a predominant inhibitory role. However, the multiple location of H3 receptors in the same tissue may lead to opposite effects on the physiologic function, thus, their role can sometimes be quite difficult to understand. As regards a possible clinical application of H3 ligands, although many suggestions have been derived from the experimental animal data (e.g. gastric disorders, asthma, myocardial ischemia, hypertension and inflammation), to date, no clinical evidence is available for any therapeutic indication. 

Allen, M.C., Graham, P., Morris, G., 1996. Histamine forming capacity (HFC) and its modulation by H3 receptor ligands in a model of bronchial hyper-responsiveness. Inflamm. Res. 45, 118-122. 

Leurs, R., Vollinga, R.C. and Timmerman, H. (1995b). The medicinal chemistry and therapeutic potentials of ligands of the histamine H3-receptor. Prog. Drug Res. 45, 107-165. 

An analogue of the classical histamine H3 antagonist thioperamide has been evaluated for its potential use as a PET ligand for the histamine H3 receptor. After attempts to fluorinate thioperamide in the cyclohexane ring failed [24], a fluoromethylated analogue of thioperamide,... 

Radiolabelled compounds for the histamine H3 receptor have been proven to be of great value in pharmacological and biochemical research. Some iodinated and tritiated compounds haven become standard research tools. In contrast, the development of PET or SPECT ligands has been proven to be troublesome. So far there has been no radiolabelled compound which is taken up into the brain in reasonable amounts to allow for PET or SPECT studies of the H3 receptor in the brain. The search for new radiolabelled compounds is still going on however, as is research to find out why these radiolabelled compounds do not enter the brain as opposed to their non-radiolabelled equivalents. One can detect pharmacological effects which can only be caused by central nervous system activity of these non-radiolabelled compounds. In view of the... 

The histamine H3 receptor has not been cloned yet and hence, virtually nothing is known about the receptor topography. However, ligand based molecular modelling studies have contributed to the understanding of the molecular features involved in ligand-receptor interaction. 

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