Biomedical subjects

X Ligneau

Publications and source records attributed to X Ligneau.

At least 37 records · Page 2Linked to original sources

PubMed2000

Substituted N-phenylcarbamates as histamine H3 receptor antagonists with improved in vivo potency.

Novel substituted N-phenylcarbamates as derivatives of 3-(1 H-imidazol-4-yl)propanol were prepared and tested for their antagonist potency in vitro and in vivo at histamine H3 receptors. Structural modifications with different alkyl and acetyl moieties were performed in an attempt to optimize pharmacodynamic and pharmacokinetic effects. Most compounds are active in a functional test for histamine H3 receptors on rat cerebral cortex synaptosomes as well as in a peripheral model on guinea pig ileum. But only carbamates without too bulky lipophilic residues showed pronounced to high antagonist potency on the enhancement of endogenous histamine in brain after p.o. administration to mice (ED50 values of 5.5 to 0.86 mg.kg-1). The tested compounds presented weak activities at histamine H1, H2, and muscarinic M3 receptors thus demonstrating their H3-receptor selectivity.

Animals↗

PubMed2000

Importance of the lipophilic group in carbamates having histamine H3-receptor antagonist activity.

In order to evaluate changes in the lipophilic part of designed carbamates concerning their potential histamine H3-receptor antagonist properties a new series of O-[3-(1H-imidazol-4-yl)propanol]carbamates was derived containing N-mono- or di-alkenyl, alkynyl, cycloalkyl, or double-branched alkyl substituents. The compounds were tested in vitro for their H3-receptor antagonist activity on synaptosomes of rat cerebral cortex and shared moderate to high antagonist activity in vitro. In this series 3-(1H-imidazol-4-yl)propyl N-(4-pentenyl)carbamate (4) was the most potent compound in vitro (Ki = 6.3 nM). H3-receptor antagonist activity in the central nervous system (CNS) was detected for most compounds in the in vivo H3-receptor assay based upon measurement of brain N tau-methylhistamine levels after p.o. administration to mice. The most effective carbamate in vivo, 3-(1H-imidazol-4-yl)propyl N-(allyl)carbamate (3), showed higher CNS potency (ED50 = 0.48 mg/kg p.o.) than the reference antagonist thioperamide. For some novel carbamates their histamine H1- and H2-receptor activities were determined on isolated organs of guinea-pig thereby demonstrating their high H3-receptor selectivity.

Animals↗

PubMed1999

Novel partial agonists for the histamine H(3) receptor with high in vitro and in vivo activity.

Novel branched N-alkylcarbamates and aliphatic ethers derived from 3-(1H-imidazol-4-yl)propanol were prepared. The compounds were investigated on two functional histamine H(3)-receptor assays. Some compounds displayed partial agonist activity on synaptosomes of rat brain cortex but behaved as pure competitive antagonists on the guinea pig ileum. Under in vivo conditions after po application to mice, some of the compounds showed partial or full agonist activity. Highest in vivo potency was found for the 3,3-dimethylbutyl ether 10 (ED(50) = 0.29 mg/kg, full intrinsic activity). These novel agonists are structurally diverse from classical aminergic histamine H(3)-receptor agonists (e.g., (R)-alpha-methylhistamine, imetit) as they lack a basic moiety in the side chain, which is supposed to be important for the activation of the receptor protein. The selectivity for the histamine H(3) receptor was proven by determination of H(1)- and H(2)-receptor activity on functional assays of the guinea pig.

Animals↗

PubMed1999

Development of chiral N-alkylcarbamates as new leads for potent and selective H3-receptor antagonists: synthesis, capillary electrophoresis, and in vitro and oral in vivo activity.

Novel carbamates as derivatives of 3-(1H-imidazol-4-yl)propanol with an N-alkyl chain were prepared as histamine H3-receptor antagonists. Branching of the N-alkyl side chain with methyl groups led to chiral compounds which were synthesized stereospecifically by a Mitsunobu protocol adapted Gabriel synthesis. The optical purity of some of the chiral compounds was determined (ee > 95%) by capillary electrophoresis (CE). The investigated compounds showed pronounced to high antagonist activity (Ki values of 4.1-316 nM) in a functional test for histamine H3 receptors on rat cerebral cortex synaptosomes. Similar H3-receptor antagonist activities were observed in a peripheral model on guinea pig ileum. No stereoselective discrimination for the H3 receptor for the chiral antagonists was found with the in vitro assays. All compounds were also screened for central H3-receptor antagonist activity in vivo in mice after po administration. Most compounds were potent agents of the H3-receptor-mediated enhancement of brain Ntau-methylhistamine levels. The enantiomers of the N-2-heptylcarbamate showed a stereoselective differentiation in their pharmacological effect in vivo (ED50 of 0.39 mg/kg for the (S)-derivative vs 1.5 mg/kg for the (R)-derivative) most probably caused by differences in pharmacokinetic parameters. H1- and H2-receptor activities were determined for some of the novel carbamates, demonstrating that they have a highly selective action at the histamine H3 receptor.

Administration, Oral↗

PubMed1998

4-Alkynylphenyl imidazolylpropyl ethers as selective histamine H3-receptor antagonists with high oral central nervous system activity.

In search for potent and therapeutically useful H3-receptor antagonists, we prepared novel 4-alkynylphenyl ether derivatives of 3-(1H-imidazol-4-yl)propanol in a convenient synthetic route. All compounds were tested for in vitro and in vivo H3-receptor antagonist activity as well as for H3-receptor selectivity versus H1- and H2-receptors. The presented 4-alkynylphenyl ethers are highly potent and selective H3 antagonists showing oral activity and improved brain penetration. Particularly 4-ethynylphenyl 3-(1H-imidazol-4-yl)propyl ether (14a) displays striking in vitro and in vivo activity with a -log Ki value of 8.6 and an ED50 value of 0.12 mg/kg. At present 14a is the most potent H3-receptor antagonist in vivo and may therefore be a potential drug for the therapy of H3-receptor-dependent diseases of the central nervous system (CNS).

Administration, Oral↗

PubMed1998

General construction pattern of histamine H3-receptor antagonists: change of a paradigm.

Novel omega-phenyl substituted and unsubstituted alkyl and alkenyl imidazole derivatives were prepared and tested for their antagonist activity in vitro and in vivo at histamine H3-receptors. Some compounds showed high in vitro and in vivo H3-receptor activity despite their structure bearing no polar moiety in the centre of the molecule which is a common structural feature of all other antagonists known. Quite probably there are further in vivo effects for some compounds resulting from other receptor interactions.

Animals↗

PubMed1998

Development of FUB 181, a selective histamine H3-receptor antagonist of high oral in vivo potency with 4-(omega-(arylalkyloxy)alkyl)-1H-imidazole structure.

A series of 4-(omega-(arylalkyloxy)alkyl)-1H-imidazoles and related sulphur-containing compounds have been prepared and evaluated for their histamine H3-autoreceptor antagonist in vitro potency in an assay on synaptosomes of rat cerebral cortex. In addition, the in vivo potency has been determined from the changes in N tau-methylhistamine levels in brain after p.o. administration to mice. Compounds with different alkyl chains and various aryl moities have been synthesized and tested to explore structure-activity relationships. Within this series of novel antagonists, (1H-imid-azol-4-yl)methyl and 2-(1H-imidazol-4-yl)ethyl ether derivatives showed low to moderate H3-receptor antagonist potency, whereas the corresponding allyl and propyl derivatives were compounds with high antagonist in vitro potency. Corresponding thioether or sulphoxide derivatives also showed antagonists activity. Additionally, some ether derivatives possessed high in vivo potency as well. The most active ether derivatives under in vivo conditions were 4-(3-(3-(4-fluorophenyl)propyloxy)propyl)-1H-imidazole (11b) and the corresponding chloro compound 11c (FUB 181) with ED50 values of 0.76 and 0.80 mg/kg, respectively. On the other hand, all compounds tested showed weak activity at histamine H1 or H2 receptors. Furthermore, the most promising ether FUB 181 exhibited low activity at adrenergic alpha 1, beta 1/2, serotonergic 5-HT2A, 5-HT3, and muscarinic M3 receptors. Time-course investigations of FUB 181 in mice showed a rapid mode of action with the highest value 3 h after p.o. application. Thus, FUB 181 appears to block histamine H3 receptors potently and selectively.

Administration, Oral↗

PubMed1998

Synthesis of potent non-imidazole histamine H3-receptor antagonists.

Histamine has been converted into a non-imidazole H3-receptor histamine antagonist by addition of a 4-phenylbutyl group at the N alpha-position followed by removal of the imidazole ring. The resulting compound, N-ethyl-N-(4-phenylbutyl)amine, remarkably has a Ki = 1.3 microM as an H3 antagonist. Using this as a lead compound, a novel series of homologous O and S isosteric tertiary amines was synthesised and structure-activity studies furnished N-(5-phenoxypentyl)pyrrolidine (Ki = 0.18 +/- 0.10 microM, for [3H]histamine release from rat cerebral cortex synaptosomes) which, more importantly, was active in vivo. Substitution of NO2 into the para position of the phenoxy group gave N-(5-p-nitrophenoxypentyl)pyrrolidine, UCL 1972 (Ki = 39 +/- 11 nM), ED50 = 1.1 +/- 0.6 mg/kg per os in mice on brain tele-methylhistamine levels.

Administration, Oral↗

PubMed1998

Neurochemical and behavioral effects of ciproxifan, a potent histamine H3-receptor antagonist.

Ciproxifan, i.e., cyclopropyl-(4-(3-1H-imidazol-4-yl)propyloxy) phenyl) ketone, belongs to a novel chemical series of histamine H3-receptor antagonists. In vitro, it behaved as a competitive antagonist at the H3 autoreceptor controlling [3H]histamine release from synaptosomes and displayed similar Ki values (0.5-1.9 nM) at the H3 receptor controlling the electrically-induced contraction of guinea pig ileum or at the brain H3 receptor labeled with [125I]iodoproxyfan. Ciproxifan displayed at least 3-orders of magnitude lower potency at various aminergic receptors studied in functional or binding tests. In vivo, measurement of drug plasma levels, using a novel radioreceptor assay in mice receiving ciproxifan p.o. or i.v., led to an oral bioavailability ratio of 62%. Oral administration of ciproxifan to mice enhanced by approximately 100% histamine turnover rate and steady state level of tele-methylhistamine with an ED50 of 0.14 mg/kg. Ciproxifan reversed the H3-receptor agonist induced enhancement of water consumption in rats with and ID50 of 0.09 +/- 0.04 mg/kg, i.p. In cats, ciproxifan (0.15-2 mg/kg, p.o.) induced marked signs of neocortical electroencephalogram activation manifested by enhanced fast-rhythms density and an almost total waking state. In rats, ciproxifan enhanced attention as evaluated in the five-choice task performed using a short stimulus duration. Ciproxifan appears to be an orally bioavailable, extremely potent and selective H3-receptor antagonist whose vigilance- and attention-promoting effects are promising for therapeutic applications in aging disorders.

Animals↗

PubMed1997

Bioavailability, antinociceptive and antiinflammatory properties of BP 2-94, a histamine H3 receptor agonist prodrug.

(R)alpha-Methylhistamine [(R)alpha-MeHA], a potent and selective histamine H3 receptor agonist in vitro and in vivo in rodents, was found to display comparatively low plasma level in healthy human volunteers, attributable to an extensive methylation of the drug's imidazole ring by histamine-N-methyltransferase. To limit this inactivation process, BP 2-94, ie., (R)-(-)-2-[[N-[1-(1H-imidazol-4-yl)-2-propyl]imino]phenylmethyl] phenol, was selected as a prodrug. A sensitive radioimmunoassay was developed to study the generation of (R)alpha-MeHA slowly released from BP 2-94 in vitro and in vivo by chemical hydrolysis. In mice after oral administration of BP 2-94 high levels of both prodrug and (R)alpha-MeHA were detected in plasma and various tissues except in the brain. In humans receiving 0.1 mmol BP 2-94 orally, plasma levels of (R)alpha-MeHA-like immunoreactivity decayed with a t(1/2) more than 24 hr, the area under the curve being two orders of magnitude higher than after oral administration of (R)alpha-MeHA. BP 2-94 displayed antiinflammatory and antinociceptive properties in rodents, related to the H3 receptor stimulation. It dose-dependently inhibited capsaicin-induced plasma protein extravasation in many rat tissues with ED50s of 0.6 to 14 micromol/kg p.o., and maximal reductions by 35 to 87%. BP 2-94 also reduced zymosan-induced paw swelling in mice with an ED50 of 1 micromol/kg p.o. and showed marked activity in the phenylbenzoquinone-induced writhing (ED50 = 0.03 micromol/kg, p.o.) or formalin tests in mice, but not in the hot plate jump test. From its pharmacokinetics and pharmacological profile BP 2-94 appears to be a promising novel therapeutic agent in disorders such as asthma, migraine or a variety of inflammatory diseases and pain associated with these disorders.

Adult↗

PubMed1997

Search for novel leads for histamine H3-receptor antagonists: amine derivatives.

In search for novel leads for histamine H3-receptor antagonists a number of amine derivatives of different (1 H-imidazol-4-yl)anilines and omega-(1 H-imidazol-4-yl)alkanamines were prepared. Pharmacological in vitro H3-receptor investigations of the prepared urea, amide, inverse amide, thioamide, and thiourea derivatives on synaptosomes of rat cerebral cortex proved that the aniline derivatives are inactive at H3-receptors, whereas derivatives of the omega-(1 H-imidazol-4-yl)-alkanamines showed moderate to good activity. Some compounds are active in the nanomolar concentration range. The most potent compounds in this series are the thioamide derivative 7 and the urea derivatives 11, 12 of 3-(1 H-imidazol-4-yl) propanamine. Therefore, the urea derivatives were tested in vitro on isolated organs of the guinea pig for their activity on the other two histamine receptor subtypes proving their high selectivity. In vivo studies of the effects of the urea derivatives 11 and 12 on brain Nt-methylhistamine levels, a test of central H3-receptor activity after peroral application to mice, showed no detectable activity. Thus, the urea type antagonists are useful potent and selective H3-receptor tools for in vitro studies and for investigations of ligand-receptor interactions.

Animals↗

PubMed1997

Search for novel leads for histamine H3-receptor antagonists: oxygen-containing derivatives.

This study was performed in order to develop new leads for antagonists of the histamine H3-receptor subtype. omega-(1 H-Imidazol-4-yl)alkyl derivatives with ester, ketone or alcohol functionality in the side chain were synthesized and tested concerning their H3-receptor antagonist activity on synaptosomes of rat cerebral cortex. The novel compounds, which possess no nitrogen-containing polar group in the side chain of the imidazole moiety, presented moderate to high antagonist potency in vitro. In this series 3-(1 H-imidazol-4-yl)propyl-3-cyclopentylpropanoate (4) was the most potent compound in vitro with -log Ki = 8.5. Unfortunately, no central antagonist H3-receptor activity was detectable for ester derivatives in the in vitro H3-receptor assay based upon measurement of brain N tau-methylhistamine levels after p.o. administration to mice. Some of these novel antagonists are useful tools for investigations on ligand-receptor interaction because of their distinct receptor activities. On the other hand, the ketone derivative 1-(1 H-imidazol-4-yl)-7-phenyl-4-heptanone (9) in vitro presented an ED50-value of 3.5 +/- 1.5 mg/kg p.o. thus proving to be a new lead for further drug investigations. The most potent compounds in vitro and in vivo also showed high H3-receptor selectivity when tested at other histamine receptor subtypes.

Animals↗

PubMed1996

Rat cerebral mast cells undergo phenotypic changes during development.

The evolution of rat cerebral mast cell phenotype during development was studied using antibodies against the granule chymases, rat mast cell protease I (RMCP-I) and rat mast cell protease II (RMCP-II) and their gene transcripts, as markers for serosal and mucosal mast cells, respectively. In situ hybridization using specific oligoprobes for RMCP-II permitted visualization of RMCP-II mRNA-containing cells as early as day 15 of embryonic development (E15). From E19 to day 4 postpartum (D4) their number increased whilst they migrated from the pia mater to the choroid fissure; at D8 cells expressing RMCP-II gene transcripts were no longer observed. The 3'-end untranslated nucleotide sequence of the RMCP-I cDNA was established in order to design selective cDNA probes for Northern blot analysis of both enzymes. Northern blot analysis revealed a strong expression of RMCP-I and RMCP-II mRNAs at D2. At D4, RMCP-I mRNA expression was still high, whereas that of RMCP-II was decreased. In adult brain, mRNA expression for both proteases was low, but detectable. Quantification of both proteases by ELISA showed that, from E19 to D4, levels of RMCP-II were maximal at E19 and remained constant until D4, whereas RMCP-I increased as a function of age. Thereafter, levels of both proteases decreased progressively, but were still present in the adult brain, with RMCP-II being uniformly distributed and RMCP-I concentrated in the thalamus. Immunohistochemical staining showed RMCP-II-immunoreactive cells within the pia mater at E19; on D2 and D4, cells with both RMCP-I and RMCP-II immunoreactivities were found within the choroid fissure and from D8, only RMCP-I-immunoreactive mast cells were observed. In the thalamus of adult rats, the latter had a perivascular localization. This study shows that in the adult, both types of mast cells are present, although in small numbers, except for RMCP-I-immunoreactive mast cells which are abundant in the thalamus. The changes in the number and phenotype of cerebral mast cells may result from the influence of a number of growth factors during development.

Amino Acid Sequence↗

PubMed1996

A novel series of (phenoxyalkyl)imidazoles as potent H3-receptor histamine antagonists.

[[(4-Nitrophenyl)X]alkyl]imidazole isosteres (where X = NH, S, CH2S, O) of previously described [[(5-nitropyrid-2-yl)X]ethyl]imidazoles (where X = NH, S) have been synthesized and evaluated for H3-receptor histamine antagonism in vitro (Ki for [3H]histamine release from rat cerebral cortex synaptosomes) and in vivo (ED50 per os in mice on brain tele-methylhistamine levels). Encouraging results led to the synthesis and testing of a novel series of substituted (phenoxyethyl)- and (phenoxypropyl)imidazoles. From the latter, 4-[3-(4-cyanophenoxy)propyl]-1H-imidazole (10a, UCL 1390; Ki = 12 nM, ED50 = 0.54 mg/kg) and 4-[3-[4-(trifluoromethyl)-phenoxy]propyl]-1H-imidazole (10c, UCL 1409; Ki = 14 nM, ED50 = 0.60 mg/kg) have been selected as potential candidates for drug development. For 16 [(aryloxy)ethyl]imidazoles the relationship between in vitro and in vivo potency is described by the equation log ED50 = 0.47 log Ki + 0.20 (r = 0.78).

Animals↗

PubMed1996

[125I]iodoproxyfan and related compounds: a reversible radioligand and novel classes of antagonists with high affinity and selectivity for the histamine H3 receptor.

The synthesis and biological evaluation of new histamine H3 receptor antagonists with an iodinated aryl partial structure are described as part of an extensive research program to find model compounds for the development of a new radioligand with high H3 receptor affinity and specific activity. All compounds were tested for their H3 receptor antagonist activity in a [3H]-histamine-release assay with synaptosomes from rat cerebral cortex. The new leads with potent H3 receptor antagonist activity belong to a series of derivatives of 3-(1H-imidazol-4-yl)propanol with carbamate (4-7), ester (8-16), and ether (17-22) as functional groups. Structure-activity relationships are discussed. The most active compound in the functional test (-log Ki = 8.3) and in binding studies with [3H]-(R)-alpha-methylhistamine on rat cerebral cortex (-log Ki = 9.0) in vitro was 3-(1H-imidazol-4-yl)propyl (4-iodophenyl)methyl ether (iodoproxyfan, 19) exhibiting no central H3 receptor antagonist activity in vivo. The potency of iodoproxyfan is more than 300 times lower at H1, H2, alpha1, alpha2, beta1, 5-HT2A, 5-HT3, and M3 receptors than at histamine H3 receptors. Because of the high potency and selectivity of 19, this compound has also been prepared in the [125I]-iodinated form by a nucleophilic halogen exchange reaction using the corresponding bromo derivative 22 as a precursor. The newly prepared [125I]iodoproxyfan (23) possesses advantageous pharmacological properties and fulfills all criteria of a useful radioligand.

Animals↗

PubMed1996

Novel carbamates as potent histamine H3 receptor antagonists with high in vitro and oral in vivo activity.

The known histamine H3 receptor antagonists burimamide, thioperamide, clobenpropit, and a related homohistamine thioamide derivative were taken as templates in search for new leads. Novel histamine H3 receptor antagonists structurally described as carbamate derivatives of 3-(1H-imidazol-4-yl)propanol were prepared in high yields by treatment of the alcohol with corresponding isocyanates or carbamoyl chlorides and investigated for their H3 receptor antagonist activity. Different chain lengths and various substituents possessing different electronic and steric parameters were introduced and structure-activity relationships established. In different functional tests, the new antagonists showed high H3 receptor antagonist potencies in vitro (-log Ki values of 6.4-8.4) at synaptosomes of rat cerebral cortex and low activities at histamine H1 and H2 receptor subtypes. They were also screened for their central in vivo activity in mice after peroral administration. The most promising compounds (2, 16, 19) showed ED(50) values of about 1-2 mg/kg and thus are potential drugs for the therapy of H3 receptor dependent diseases. Some of the novel carbamate derivatives are H3 receptor selective compounds with high in vitro and in vivo activity.

Administration, Oral↗

PubMed1995

Design of potent non-thiourea H3-receptor histamine antagonists.

Starting from thioperamide, the first potent and selective H3-receptor histamine antagonist, analogues have been synthesized and tested in vitro on rat cerebral cortex to explore structure-activity relationships. The aim has been to design potent compounds which do not possess the thiourea group of thioperamide and which may have improved brain penetration. In a short series of open chain thiourea analogues, the optimum chain length for H3-antagonist potency was found to be (CH2)3. Compounds derived from histamine and possessing an aromatic nitrogen-containing heterocycle on the side chain amino group in place of thiourea show H3-antagonist activity. Furthermore, when the heterocycle is 2-pyridyl, electron-withdrawing substituents (e.g. NO2, CF3, CO2Me) in the pyridine 5-position increased potency. The synthesis of 4-[4(5)-imidazolyl]piperidine and its conversion into the (trifluoromethyl)pyridyl analogue 5b of thioperamide is described; however, 5b is not as potent as thioperamide. Replacing imidazole by pyridine or substituting imidazole on the remote N considerably reduced potency. Replacing the side-chain NH by S increased potency still further and the most potent compound is 2-([2-[4(5)-imidazolyl]ethyl]thio)-5-nitropyridine (UCL 1199) which has Ki = 4.8 nM.

Animals↗

PubMed1995

Azines and diazines 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, azines and diazines with ether (6-13) and carbamate (15-24) moieties as functional groups were synthesized. The obtained compounds did not show significant H3-receptor antagonist activity in vitro (rat brain cortex) or in vivo (mice brain). 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.

Animals↗