4-benzyl-1H-imidazoles with oxazoline termini as histamine H3 receptor agonists.

Research on the therapeutic applications of the histamine H3 receptor (H3R) has traditionally focused on antagonists/inverse agonists. In contrast, H3R agonists have received less attention despite their potential use in several disease areas. The lower availability of H3R agonists not only hampers their full therapeutic exploration, it also prevents an unequivocal understanding of the structural requirements for H3R activation.

Synthesis and structure-activity relationship of the first nonpeptidergic inverse agonists for the human cytomegalovirus encoded chemokine receptor US28.

US28 is a human cytomegalovirus (HCMV) encoded G-protein-coupled receptor that signals in a constitutively active manner. Recently, we identified 1 [5-(4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl)-2,2-diphenylpentanenitrile] as the first reported nonpeptidergic inverse agonist for a viral-encoded chemokine receptor. Interestingly, this compound is able to partially inhibit the viral entry of HIV-1.

Synthesis of benzylideneacetophenones and their inhibition of lipid peroxidation.

A series of benzylideneacetophenone derivatives have been synthesized and found to show potent inhibition of the lipid peroxidation (LPO) in rat liver microsomes. All 19 compounds prepared in this series are LPO inhibitors. The highest activity was found in para hydroxy derivatives with two meta tert-butyl substituents.

Isoquinoline and quinazoline urea analogues as antagonists for the human adenosine A(3) receptor.

Isoquinoline and quinazoline urea derivatives were found to bind to human adenosine A(3) receptors. Series of N-phenyl-N'-quinazolin-4-ylurea derivatives and N-phenyl-N'-isoquinolin-1-ylurea derivatives were synthesized and tested in radioligand binding assays on their adenosine receptor affinities. A structure-affinity analysis indicated that on the 2-position of the quinazoline ring or the equivalent 3-position of the isoquinoline ring a phenyl or heteroaryl substituent increased the adenosine A(3) receptor affinity in comparison to unsubstituted or aliphatic derivatives.

Selective ligands as tools to study histamine receptors.

In this review the histaminergic ligands for the histamine H(1), H(2) and H(3) receptors, which are currently used as tools in pharmacological studies, are described. To study interactions with the histamine H(1) receptor, the H(1) agonist 2-aminoethylthiazole has long since been used. However, during the last decade, 2-phenylhistamine derivatives emerged with interesting binding features.

Effect of clobenpropit, a centrally acting histamine H3-receptor antagonist, on electroshock- and pentylenetetrazol-induced seizures in mice.

The anticonvulsant activity of clobenpropit, an isothiourea derivative of histamine and potent H3-receptor antagonist, was investigated in two representative seizure models in mice. In the maximal electroshock seizure threshold test, clobenpropit dose-dependently raised the electroconvulsive threshold for tonic (hindlimb extension) seizures, but a significant increase of about 15% was determined only at the high dose of 40 mg/kg i.p.

A novel class of adenosine A3 receptor ligands. 2. Structure affinity profile of a series of isoquinoline and quinazoline compounds.

1-Substituted 3-(2-pyridinyl)isoquinolines have been shown to form a novel class of adenosine A3 receptor ligands. In the present study further investigations of this new lead and the structure affinity relationships of this class of compounds are described. First, the influence of an amide group at position 1 of the isoquinoline ring on the adenosine A3 receptor affinity was determined.

A novel class of adenosine A3 receptor ligands. 1. 3-(2-Pyridinyl)isoquinoline derivatives.

A series of 3-(2-pyridinyl)isoquinoline derivatives was synthesized as potential antagonists for the human adenosine A3 receptor by substitution of the 1-position. The compounds were obtained by various synthetic routes from 1-amino-3-(2-pyridinyl)isoquinoline. The affinity was determined in radioligand binding assays for rat brain A1 and A2A receptors and for the cloned human A3 receptor.

Development of an ear edema model of contact hypersensitivity to avoid false-positive results due to interactions between hapten and test agents.

Ear edema models are regularly used for topical testing of antiinflammatory compounds. However, test compounds are usually applied simultaneously with proinflammatory agents at the same site which may result in mutual interactions. In order to avoid the occurrence of false antiinflammatory effects, a model of oxazolone-induced contact hypersensitivity has been described in which the hapten and test compound are each applied separately to only one side of the ear.

The agonistic binding site at the histamine H2 receptor. I. Theoretical investigations of histamine binding to an oligopeptide mimicking a part of the fifth transmembrane alpha-helix.

Mutation studies on the histamine H2 receptor were reported by Gantz et al. [J. Biol.

Structure-activity relationships for the glutathione conjugation of 2-substituted 1-chloro-4-nitrobenzenes by rat glutathione S-transferase 4-4.

In the present study structure--activity relationships (SAR's) are described for the experimentally determined kinetic parameters (Km, kappa cat, and kappa cat/Km) of the GST 4-4-catalyzed reaction between GSH and 10 2-substituted 1-chloro-4-nitrobenzenes. Steric, lipophilic, and electronic parameters were correlated with the kinetic parameters. Moreover, charge distributions and several energy values were calculated for the substrates and the corresponding Meisenheimer intermediates with MeS- as a model nucleophile for the thiolate anion of GSH and used in the regression analyses.

Inhibition of growth of Histoplasma capsulatum yeast cells in human macrophages by the iron chelator VUF 8514 and comparison of VUF 8514 with deferoxamine.

Histoplasma capsulatum requires intracellular iron to survive and multiply within human and murine macrophages (M phi). Thus, iron chelators may be useful compounds in the treatment of histoplasmosis. In the present study we compared the efficacies of five different iron chelators with deferoxamine (DEF) for their capacity to inhibit the growth of H.

Influence of membrane composition of various parasites on the inhibitory activity of a series of bipyridyl analogues.

In a previous report the dependence of the antimycoplasmal activity of bipyridyl analogues on the presence of Cu+ ions has been shown. The inhibitory activity of these compounds has now been studied against Escherichia coli mycobacteria and Candida albicans in the absence and presence of Cu2+ ions using growth kinetic techniques. It was found that the inhibitory activity against E.

New activation model for the histamine H2 receptor, explaining the activity of the different classes of histamine H2 receptor agonists.

Recently we developed amthamine [2-amino-5-(2-aminoethyl)-4-methylthiazole]. This cyclic analogue of dimaprit proved to be the most potent and selective histamine H2 receptor agonist of a series of substituted 4- or 5-(2-aminoethyl)thiazoles. Quantum chemical studies on histamine (N pi-H tautomer), dimaprit, and amthamine revealed that, based upon geometries of molecular electrostatic potentials, it is likely that these agonists accept a proton from the proton-donating receptor site on their double-bonded (heteroaromatic) nitrogen atoms.

Histamine H2-receptor agonists. Synthesis, in vitro pharmacology, and qualitative structure-activity relationships of substituted 4- and 5-(2-aminoethyl)thiazoles.

It is well known that both histamine and dimaprit show moderate histamine H2-receptor agonistic activities on the guinea pig right atrium. Quantum chemical calculations on these two compounds showed similarities in electron distributions and molecular electrostatic potentials (MEP's), which could be extended to rigid analogues [2-amino-5-(2-aminoethyl)thiazoles] of the latter structure. On the base of these results a series of substituted 4- and 5-(2-aminoethyl)thiazoles was synthesized applying small alkyl substitution variations as reported for histamine.

Synthesis and copper-dependent antimycoplasmal activity of amides and amidines derived from 2-amino-1,10-phenanthroline.

A series of both aliphatic and aromatic amides and aromatic amidines derived from 2-amino-1,10-phenanthroline (3) according to the Topliss scheme were synthesized and subsequently tested for antimycoplasmal potency. Although the compounds themselves showed no activity, in the presence of a nontoxic copper concentration of 40 microM all compounds appeared to be very active against Mycoplasma gallisepticum K154. The most active compounds were found in the amide series and show growth inhibition in the nanomolar range.

4- or 5- (omega-aminoalkyl) thiazoles and derivatives; new selective H2-receptor agonists.

It is well known that both histamine and dimaprit show moderate H2-receptor agonistic activity (guinea pig right atrium). Quantum chemical calculations indicated that 2-aminothiazole derivatives that might be regarded as cyclic dimaprit analogues, should possess H2-receptor agonistic activity as well. In the present study a series of 4- or 5-(omega-aminoalkyl) thiazoles has been synthesized, showing a moderate to strong H2-receptor agonistic activity as compared to histamine whereas no activity on H1- and H3-receptors could be detected.

New selective histamine H1 agonists. Synthesis and pharmacology.

In this article the synthesis and histaminergic H1 activity of a series of substituted 2-phenylhistamines are described. It appeared that substitution of the phenyl ring of these compounds influences the H1 activity substantially. In general, substitution in para position causes a decrease in H1 activity.

Copper complexes of 1,10-phenanthroline and related compounds as superoxide dismutase mimetics.

In a preliminary study we tested CuSO4.5H2O, (Cu(II]2[3,5-diisopropylsalicylate]4.2H2O and a number of copper complexes of substituted 1,10-phenanthrolines for superoxide anion dismutase activity.

Synthesis and copper-dependent antimycoplasmal activity of 1-amino-3-(2-pyridyl)isoquinoline derivatives. 2. Amidines.

In our search for new compounds with antimycoplasmal activity, a series of aromatic amidines derived from 1-amino-3-(2-pyridyl)isoquinoline (1) was synthesized. In the presence of 40 microM copper the most active compounds show growth inhibition of Mycoplasma gallisepticum in the nanomolar range. These compounds are 3 times as active as tylosin, an antimycoplasmal therapeutic agent that is used in veterinary practice.

Studies on histaminergic compounds, Part VII. Histamine H2-binding on guinea-pig cerebral cortex compared to histamine (ant)agonism.

The pKD values of series of H2-active compounds, obtained from displacement curves of 3H-tiotidine from a guinea-pig cerebral cortex homogenate were compared with the pA2/pD2 values of these compounds on the right atrium of the same animal species. A good correlation was found between the cortex pKD value and the pharmacological activity on the right atrium, especially with the antagonists, the partial agonists and the agonistic impromidine analogues (guanidines). The poor correlation between cortex pKD and atrium pD2 of some other agonists (the amines) might be explained by the presence of spare receptors for these compounds.

Synthesis and copper-dependent antimycoplasmal activity of 1-amino-3-(2-pyridyl)isoquinoline derivatives. 1. Amides.

In order to investigate the antimycoplasmal activity of compounds structurally related to 2,2'-bipyridyl, a series of both aliphatic and aromatic amides derived from 1-amino-3-(2-pyridyl)isoquinoline were synthesized. The most active compounds appeared to be as active as Tylosin, an antimycoplasmal therapeutic that is used in veterinary practice, in the presence of a small nontoxic amount of copper. Furthermore, it was found that antimycoplasmal activity depends on the hydrophobic fragmental value of amide residue.

Investigation into the mechanism of copper uptake by Mycoplasma gallisepticum in the presence of 2,9-dimethyl-1,10-phenanthroline.

In the presence of copper certain 2,2'-bipyridyls show antimycoplasmal activity, whereas copper itself causes a toxic effect. In this paper results are presented to elucidate the mechanism of copper uptake in the presence of 2,9-dimethyl-1,10-phenanthroline. The time course of copper and/or ligand uptake under the applied conditions is consistent with a carrier transport mechanism in which 2,9-dimethyl-1,10-phenanthroline operates as a carrier for copper ions.