H3 ligands

The definitive identifieation of a therapeutie raison d etre for H3 antagonists will happen in the elinie. A handful of H3 ligands are reported to have entered elinieal testing. ABT-834 entered Phase-I trials for the indieation of cognitive disorders in May 2003 but no news has been reported since that time. GT-2331 (11) was approved for Phase-II clinical trials in 1999 but no news has been reported since then [4]. At this point, there are no data available to assess the therapeutic potential in human disease (See Table 5.1). 

In conclusion, H3 ligands offer the attractive vista of multiple applications in various disorders, but the ultimate definition of their therapeutic utility will have to await clinical trial results. Future work will determine whether inverse agonists, neutral antagonists, or protean agonists will constitute the more useful pharmacological intervention. 

Further modifications of (26) led to the oxadiazoles as depicted by (28) [94]. Some of the oxadiazoles have improved human H3 affinity and (28) is efficacious in the dipsogenia model after i.p. administration. However, the molecular weight and log P of these H3 ligands is rather high. 

The first step in hydroformylation with the rhodium catalyst involves the loss of a P

hydrogen transfer that is accompanied by a change... 

Acoustic emission diazine metal complexes, 80 Acrylonitrile metal complexes, 263 Actinide complexes cupferron, 510 dimethyl sulfoxide IR spectra, 490 phosphines SHAB theory, 1040 phthalocyanines, 864 thiocyanates, 236 Actins, 973 Acylates H3-ligands... 

A synopsis of the most important data concerning H3 receptors and gastric acid secretion is reported in Tables 1 and 2. Table 3 reports the effects of H3 ligands on hormonal or paracrine secretions which are directly or indirectly connected with acid secretion. 

Experiments carried out in the conscious rat demonstrated that H3 receptors contribute only to the central, and not the peripheral, regulation of intestinal motility (Fargeas et al., 1989). In addition, the concomitant ineffectiveness on acid secretion of peripherally administered H3 ligands seems to exclude a significant role of H3 receptors in the peripheral regulation of gastrointestinal functions. Lastly, in the mouse H3 receptors do not seem to have any appreaciable influence on gastrointestinal motility (Oishi et al., 1993)... 

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). 

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. 

Therefore, H3 ligands still represent an unusual set of orphan drugs . All the same, a selective modulation of neurotransmission in a specific tissue by means of more and more selective ligands, could still represent an innovative possibility for therapeutic intervention. 

All potent H3 ligands posses an imidazole ring. In it s neutral form, the imidazole can exist in two tautomeric forms (Nre and NT, respectively). At present, it is not clear which tautomeric form is recognised by the receptor. 

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