Biomedical subjects

X Ligneau

Publications and source records attributed to X Ligneau.

41 records · Page 3Linked to original sources

PubMed1995

Pyrazoles as potential histamine H3-receptor antagonists.

In search of structure-activity relationships among histamine H3-receptor antagonists, the imidazole ring of known H3-receptor antagonists was replaced by different heteroaromatic ring systems. Thus, pyrazoles with ether (4,5) and carbamate (6,7) moieties as functional groups were synthesized. Reaction of the hydrochloride of 4-(3-hydroxypropyl)pyrazole (1) with phenyl or benzyl isocyanates mainly gave the carbamates 6 and 7, whereas a similar reaction with 1 as the free base furnished the N-carbamoylpyrazoles 8 and 9. The bifunctional pyrazoles 10 and 11 were formed as by-products. The compounds obtained did not show significant H3-receptor antagonist activity in vitro (rat brain cortex) or in vivo (mouse brain). These results demonstrate the importance of the imidazole moiety for H3-receptor antagonists. The new compounds were also screened for H1-receptor antagonist activity on the isolated guinea-pig ileum and for H2-receptor antagonist activity on the isolated spontaneously beating guinea-pig right atrium. The substances showed only weak antagonistic activity at both histamine receptors H1 and H2.

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PubMed1994

[125I]iodoproxyfan, a new antagonist to label and visualize cerebral histamine H3 receptors.

Iodoproxyfan, i.e., 3-(1H-imidazol-4-yl)propyl-(4-iodophenyl)-methyl ether, is a novel potent and selective histamine H3 receptor antagonist. [125I]Iodoproxyfan binding to membranes of the rat striatum was reversible and saturable. Specific binding defined with 1 microM (R)-alpha-methylhistamine corresponded to 65% of the total at 30 pM. Scatchard analysis indicated a Kd of 65 pM and maximal binding capacity of 78 fmol/mg of protein. The specificity of [125I]Iodoproxyfan binding to H3 receptors was demonstrated by its pharmacological profile. A series of H3 receptor agonists inhibited [125I]iodoproxyfan binding with a similar maximal effect and with the expected order of potency and stereoselectivity ratio. H3 receptor antagonists inhibited the specific binding with the expected Ki values. In the presence of guanylnucleotides, 40% of sites exhibited a approximately 40-fold lower affinity for histamine, indicating that the H3 receptor belongs to the superfamily of G protein-coupled receptors and revealing the existence of two populations of sites. Well contrasted autoradiographic pictures of total [125I]iodoproxyfan binding to sections of the rat brain were obtained in a short time and over a low nonspecific binding. The heterogenous distribution of H3 receptors with high labeling of anterior cerebral cortex, ventral striatum and other limbic areas was confirmed. In addition, a clearly distinguishable laminated pattern of labeling was evidenced in the cerebral cortex and hippocampal formation. Hence, this new probe should be useful for sensitive assay and localization of the H3 receptor.

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PubMed1992

S-[2-(4-imidazolyl)ethyl]isothiourea, a highly specific and potent histamine H3 receptor agonist.

The effects of a new agonist of histamine (HA) H3 receptors, Imetit (S-[2-(4-(imidazolyl)ethyl]isothiourea) were investigated in vitro and in vivo and compared to those of (R)-alpha-methylhistamine [(R)-alpha-MeHA], a prototypic drug. Imetit inhibited the binding of [3H](R-alpha-MeHA to rat brain membranes with a Ki value of 0.1 +/- 0.01 nM. The release of endogenously synthesized [3H]HA induced by K(+)-depolarization from rat brain slices and synaptosomes was inhibited by Imetit with EC50 values of 1.0 +/- 0.3 and 2.8 +/- 0.7 nM, respectively. Imetit behaved as a full agonist and was about 4 times more potent than (R)-alpha-MeHA and 60 times more potent than HA. Thioperamide, a selective H3 receptor antagonist, elicited a parallel rightward shift of the concentration-response curve for Imetit with an apparent Ki value of 5.6 +/- 1.4 nM. Imetit potencies relative to HA were less than 0.1% and only 0.6% at HA H1 and H2 receptor reference systems, respectively. Imetit was found not to be a substrate or an inhibitor of HMT. After p.o. administration to mice or rats, Imetit decreased (by approximately 50%) the tele-MeHA level in the cerebral cortex with ED50 values of 1.0 +/- 0.3 and 1.6 +/- 0.3 mg/kg, respectively. This effect was still maximal after 6 hr. The in vivo potency and duration of action of Imetit were in the same range as those of (R)-alpha-MeHA. It is therefore concluded that Imetit represents a new potent and selective HA H3 receptor agonist.

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PubMedDate not supplied

Novel histamine H3-receptor antagonists with benzyl ether structure or related moieties: synthesis and structure-activity relationships.

In search of new histamine H3-receptor ligands sixteen ether derivatives of 3-(1H-imidazol-4-yl)propanol with benzylic partial structure or related moieties were prepared and investigated as H3-receptor antagonists. The new compounds belong to a general construction pattern developed by other histamine H3-receptor antagonists. Structural modifications were introduced in an attempt to optimize in vitro as well as in vivo activity. Structure-activity relationships of the new histamine H3-receptor antagonists are discussed. All ether derivatives showed in vitro activities in the nanomolar concentration range, but only compounds with bulky lipophilic residues were also active under in vivo conditions. The most active compound within this series was 3-(1H-imidazol-4-yl)propyl 1-naphthylmethyl ether (4n) presenting an ED50 of 3.2 +/- 1.9 mg/kg regarding enhancement of endogenous histamine in brain after p.o. administration to mice. Furthermore, comparison of the H3-receptor activities measured on synaptosomes of rat cerebral cortex and on guinea pig ileum gave a good correlation indicating homogeneity of central and peripheral H3-receptor test models. The most interesting compounds were also evaluated in functional in vitro assays with regard to their activities at histamine H1-, H2-, and muscarinic M3-receptors. The tested compounds showed very weak activities at these receptor subtypes demonstrating their H3-receptor selectivity.

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PubMedDate not supplied

Structure-activity studies with histamine H3-receptor ligands.

Starting from thioperamide, the first potent and selective H3-receptor histamine antagonist, analogues have been synthesised and tested in vitro on rat cerebral cortex to explore structure-activity relationships. The aim has been to design compounds which do not possess the thiourea group of thioperamide and which may have improved brain penetration. Some compounds derived from histamine and possessing an aromatic nitrogen-containing heterocycle on the side-chain amino group show strong H3-antagonist activity. These have served as leads to provide aryloxyethyl- and aryloxy-propylimidazoles which are potent H3 antagonists of histamine. Structure-activity studies of the very potent and selective agonist, imetit (S-[2-imidazol-4-yl)ethyl]isothiourea), have explored the the transition between agonist, partial agonist and antagonist. The isosteric isourea is also a potent agonist. N,N'-Dibutyl-[S-[3-(imidazol-4-yl)propyl]isothiourea is a very potent antagonist having Ki = 1.5 nM.

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