Henk van der Goot

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. In the light of these important issues, we present our findings on 4-benzyl-1H-imidazole-based H3R agonists. Starting from two high throughput screen hits (10 and 11), the benzyl side chain was altered with lipophilic groups using combinatorial and classical chemical approaches (compounds 12-31). Alkyne- or oxazolino-substituents gave excellent affinities and agonist activities up to the single digit nM range. Our findings further substantiate the growing notion that basic ligand sidechains are not necessary for H 3R activation and reveal the oxazolino group as a hitherto unexplored functional group in H3R research.

Amselamine, a new selective histamine H2-receptor agonist

Abstract The synthesis of amselamine (2-amino-5(2-aminoethyl)-4-methyl-1,3-selenazole), a potent histamine H2-agonist, has been described. At the guinea pig right atrium amselamine revealed to be slightly more active than its sulfur analogue amthamine and histamine. Moreover negligible effects on H1 and H3-receptors were observed.

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.

SummaryMutation studies on the histamine H2 receptor were reported by Gantz et al. [J. Biol. Chem., 267 (1992) 20840], which indicate that both the mutation of the fifth transmembrane Asp186 (to Ala186) alone or in combination with Thr190 (to Ala190) maintained, albeit partially, the cAMP response to histamine. Recently, we have shown that histamine binds to the histamine H2 receptor as a monocation in its proximal tautomeric form, and, moreover, we suggested that a proton is donated from the receptor towards the tele-position of the agonist, thereby triggering the biological effect [Nederkoorn et al., J. Mol. Graph., 12 (1994) 242; Eriks et al., Mol. Pharmacol., 44 (1993) 886]. These findings result in a close resemblance with the catalytic triad (consisting of Ser, His and Asp) found in serine proteases. Thr190 resembles a triads serine residue closely, and could also act as a proton donor. However, the mutation of Thr190 to Ala190 — the latter is unable to function as a proton donor — does not completely abolish the agonistic cAMP response. At the fifth transmembrane α-helix of the histamine H2 receptor near the extracellular surface, another amino acid is present, i.e. Tyr182, so an alternative couple of amino acids, Tyr182 and Asp186, could constitute the histamine binding site at the fifth α-helix instead of the (mutated) couple Asp186 and Thr190. In the first part of our present study, this hypothesis is investigated with the aid of an oligopeptide with an α-helical backbone, which represents a part of the fifth transmembrane helix. Both molecular mechanics and ab initio data lead to the conclusion that the Tyr182/Asp186 couple is most likely to act as the binding site for the imidazole ring present in histamine.

Studies on histaminergic compounds VIII. A new series of compounds showing H1-antagonistic and H2-agonistic properties; synthesis, in vitro pharmacology and structure—activity relationships

Abstract To study the structure—activity relationships (SAR) of impromidine-like H2-agonists, we prepared some analogues of the potent agonist VUF 8405 (an analogue of impromidine in which the 5-methylimidazole moiety was replaced by a phenyl group) by replacing the benzyl group of VUF 8405 with substituted diphenylmethyl moieties and a number of related groups. The compounds have been tested for H1-activity on guinea pig ileum and trachea. To determine the H2-activity, the compounds have been investigated on both the right atrium and gastric fundus of the guinea pig. The SAR for H1-antagonistic activity of this series of compounds on the ileum was found to be analogous to that on the trachea. A significant difference was found between the H2-SAR on the right atrium and gastric fundus. Because of this combination of H1-antagonism and H2-agonism, some of these compounds might be clinically useful, for instance in the treatment of certain allergic disturbances and some kinds of heart failure.

Electron ionization mass spectrometry of curcumin analogues: an olefin metathesis reaction in the fragmentation of radical cations

The natural compound curcumin, used in cosmetics, traditional medicines and as a spice in food, is known as a multi-factorial anti-inflammatory agent. To study the anti-inflammatory activity of curcumin derivatives, 24 analogues were synthesized and their structures were confirmed by 1H NMR and electron ionization (EI) mass spectrometry. Most signals in the EI mass spectra can be attributed to commonly known fragmentations, but the formation of ring-substituted 1,2-diphenylethene (stilbene)-type radical cations, observed in the spectra of all compounds investigated and resulting in the base peak for some compounds, requires a peculiar rearrangement. Metastable ion spectra and 13C labelling studies show that the stilbene-type ions are formed directly from the molecular ions and contain the two original aryl groups and the 1 and 7 carbon atoms of the olefinic system. It is proposed that the formation of stilbene-type ions results from an intramolecular olefin metathesis reaction; this suggestion is supported by semi-empirical (MNDO/PM3) calculations.

Studies on histaminergic compounds VI. Synthesis and structure—activity relationships of a series of cimetidine and impromidine congeners

Abstract A series of congeners, resulting from the replacement of the 5-methylimidazole group of cimetidine and impromidine by a 2-guanidino-4-thiazolyl, 5-dimethylaminomethyl-2-furanyl, 2-pyridyl and a phenyl group have been synthesized and tested for histaminergic activity. From the results, it could be concluded that the ‘impromidine extra binding site’, which is thought to cause the high activity of impromidine, may not be identical to the binding site for the heterocyclic aromatic part of the H 2 -antagonists.

Investigation into the mechanism of copper uptake by Mycoplasma gallisepticum in the prescence 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. The influence of valinomycin on copper uptake indicates that the transmembrane potential is not the driving force in the carrier process.

A New Method for the Determination of Partition Coefficients of Air Sensitive Copper(I) Complexes

Determinations of log P values of copper complexes in oil/water were performed in a new, totally closed apparatus connected with a filter-probe extractor. The results indicate that the system may be generally suitable for the determination of log P values of oxidizable and nonoxidizable metal complexes. In the case of the copper (I) complexes spectrophotometric analysis was not feasible, since 1-octanol was extracted by these complexes into the aqueous phase, resulting in a change in the extinction coefficient. To establish accurately the concentration in each phase, copper was determined by atomic absorption spectrometry.