H. Van Der Goot

Isothiourea analogues of histamine as potent agonists or antagonists of the histamine H3-receptor

The synthesis and H3-activity of a series of isothiourea analogues of histamine have been described. It has been shown that S-[2-(4(5)-imidazolyl)ethylisothiourea (VUF 8325) is a potent H3-agonist measured as the electrically evoked contraction of the guinea-pig ileum. Upon methylation of the imidazole system or the isothiourea moiety a decrease in affinity was observed leading to potent H3-antagonists. Particularly the 4-chlorobenzyl group appeared to be favourable in the series described resulting in a histamine H3-antagonist with a pA2-value of 9.9.

Synthesis of some symmetrical curcumin derivatives and their antiinflammatory activity

Summary Curcumin is not only a frequently used food additive, but it is also a well-known constituent of Indonesian traditional medicines. Several beneficial effects are ascribed to curcumin, eg, its antiinflammatory properties. In order to study the antiinflammatory activity, a series of curcumin derivatives were prepared and the inhibition of the carrageenin-induced oedema by these compounds was established. It appeared that the para hydroxy groups in curcumin are important for antiinflammatory activity. This activity is enhanced when, in combination with the para hydroxy groups, the meta positions are occupied with alkyl groups. Since the methyl derivatives are more active than the corresponding ethyl and tert -butyl derivatives, it is suggested that sterical hindrance is involved.

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. So far no radiolabelled selective H(1) agonist has been commonly used. As H(1) antagonists mepyramine, triprolidine and chlorpheniramine are described together with radiolabelled H(1) antagonists [3H]mepyramine and [3H]doxepin. Special attention has been paid to the PET ligands [11C]doxepin and [11C]mepyramine and the [125I] labelled antagonists [125I]iodobolpyramine and [125I]iodoazidophenpyramine. Concerning H(2) agonists, especially dimaprit, amthamine and impromidine are discussed. There are several H(2) antagonists; amongst them cimetidine, tiotidine and ranitidine are used most frequently. Many of these antagonists behave as inverse agonists. As radiolabelled H(2) antagonists, [3H]cimetidine, [3H]tiotidine, [125I]iodoaminopotentidine and [125I]iodoazidopotentidine are included. Commonly used histamine H(3) agonists are N(alpha)-methylhistamine, (R)alpha-methylhistamine, imetit and immepip. Both methylhistamines are also available as [3H] labelled ligands. As reference compounds, often used H(3) antagonists are thioperamide, clobenpropit, iodophenpropit and impentamine. Most important radiolabelled H(3) antagonists are S-[3H]methylthioperamide, [3H]thioperamide, [125I]iodophenpropit and [125I]iodoproxyfan. The use of all these compounds as a tool in pharmacology is also discussed.

1,5-Diphenyl-1,4-pentadiene-3-ones and cyclic analogues as antioxidative agents. Synthesis and structure-activity relationship.

A series of 1,5-diphenyl-1,4-pentadiene-3-ones and cyclic analogues with OH-groups in the para position of the phenyl rings and various meta substituents were prepared and their antioxidant activity compared with that of curcumin. Most of them exhibited potent antioxidative activity, especially when all the meta positions were substituted by methoxy groups.

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.

Studies on a bioerodible drug carrier system based on polyphosphazene Part I. Synthesis

Abstract Polyphosphazenes are, due to their inorganic backbone, of considerable interest as bioerodible implantable materials. Polyphosphazenes are usually prepared by substitution of the chloro atoms in polydichlorophosphazene (PNCl2)nby nucleophiles, such as amines and aryl or alkoxy compounds. If the substituent is bound hydrolytically unstable to the phosphorus atom in the chain, the polymer degrades in vivo, yielding ammonium and phosphate ions. By selecting suitable organic substituents, e.g., amino acid esters, only products that are harmless to the body are formed. Covalently bound drugs, as substituents, turn the polymer into a bioerodible drug delivery system. To study the feasibility of this concept a polyphosphazene carrying as side groups an α-amino acid ester as well as a drug, attached to the polymer chain via a spacer, has been prepared.

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. It appeared that this activity depends on the ligands involved and might be governed by the redox potential of the Cu(I) complex/Cu(II) complex couple. The strong superoxide anion dismutase activity of Cu(II)[DMP]2 complex can be expected considering its high redox potential. Rather surprisingly is the superoxide anion dismutase activity of the Cu(I)[DMP]2 complex since it involves oxidation to Cu(II)[DMP]2 complex. From regression analysis it was established that steric and field effects of the substituents of the investigated phenanthrolines play an important role in SOD activity and therefore it is concluded that complex formation is important for the superoxide dismutase-like activity.

Histamine H2-binding on guinea pig cerebral cortex

The Kd-values of some histamine H2-active compounds, obtained from radio-ligand-binding studies on a homogenate of the guinea-pig cerebral cortex with3H-tiotidine as the labelled H2-ligand, were compared with the pA2/pD2-value of these compounds on the guinea-pig right atrium and guinea-pig isolated gastric fundus. A good correlation was found between the pKd of the H2-antagonists and their pA2 on the guinea-pig right atrium. A much poorer correlation however was obtained between the pKd of the agonists on the cerebral cortex and their pD2-values on the guinea-pig right atrium and the gastric fundus. This poor correlation between true affinity and H2-activity of the agonists might be explained by spare receptors as a much better correlation was obtained between pKd and pD2 of partial agonists.

Studies on a bioerodible drug carrier system based on a polyphosphazene: Part III. Experiments in vivo

Abstract Polyphosphazenes containing amino acid ester substituents as well as naproxen are of particular interest as implantable bioerodible devices for controlled release of drugs. To study the influence of enzymatic activity on the release rate, experiments are performed in plasma of rats. A significant acceleration of the release rate is observed, although the total release remains constant (over the time interval measured). Biocompatibility is an urgent necessity for implantable devices. In order to study the acceptability of two bioerodible polyphosphazenes, one containing naproxen, the other only amino acid ester substituents, implantation studies in rats were performed. A good acceptability was observed. To study the release of naproxen in vivo a polymeric device was implanted in rats and the urine as well as plasma naproxen levels were determined in time. After an initially higher release, a very slow, probably constant release of naproxen was observed. Some pharmacokinetic calculations are presented. They are in agreement with literature data.

Mechanism of action of the copper(I) complex of 2,9-dimethyl-1,10-phenanthroline on Mycoplasma gallisepticum.

Evidence was found that the inhibitory action of Cu(DMP)2NO3, the copper(I) complex of 2,9-dimethyl-1,10-phenanthroline (DMP), on Mycoplasma gallisepticum is a consequence of the ultimate toxicity of copper, and not that of the ligand, DMP. From uptake studies with radiolabeled 67Cu and [14C]DMP, we concluded that significantly more copper than DMP is bound to the mycoplasmal cell. It appeared that dissociation of Cu(DMP)2+ occurred shortly after interaction with the cell membrane. Copper was transported across the cytoplasmic membrane. A strong dependence of copper uptake on the incubation medium was observed in the absence of DMP. The main function of the ligand DMP appeared to be as a vehicle for the transport of copper from nontoxic copper-medium complexes to membrane-buried cellular ligands.