Histamine H3 ligands

Kurihara reported imidazomethyl phosphonates 35 as another HWE-type reagents. The 35 reacted readily with various aldehydes and ketons in the presence of t-BuOK to produce ( )-vinylimiazoles 36 in good to excellent yields. The reactions of 35 with all substrates, aliphatic aldehydes, aromatic and heteroaromatic aldehydes, provided substituted ( )-vinylimidazoles. The synthetic utility of the reagent 35 was demonstrated by the efficient preparation of few histamine H3 ligands (37) by simple hydrogenation of intermediate 36. 

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

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. 

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... 

In the rat anaphylactic histamine release from peritoneal mast cells is reduced by (R)a-methylhistamine, and this effect is reversed by thioperamide. Therefore, H3 receptors seem to be responsible for the negative feedback regulation of histamine release from rat peritoneal mast cells. However, the high concentrations of the H3 agonist necessary to elicit this effect, suggest that H3 receptors on the rat peritoneal mast cells are a subtype distinct from those in the rat brain. Contrastingly, histamine release induced by compound 48/80 was not altered by H3 ligands (Kohno et al., 1994). 

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. 

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. 

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. 

These compounds are valuable intermediates for the synthesis of histamine H3- and H2-ligands. 

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... 

Molecular modelling studies of histamine H3 receptor ligands... 

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