Heinz H. Pertz

17-β-Estradiol Inhibits Transforming Growth Factor-β Signaling and Function in Breast Cancer Cells via Activation of Extracellular Signal-Regulated Kinase through the G Protein-Coupled Receptor 30

Breast cancer development and breast cancer progression involves the deregulation of growth factors leading to uncontrolled cellular proliferation, invasion and metastasis. Transforming growth factor (TGF)-β plays a crucial role in breast cancer because it has the potential to act as either a tumor suppressor or a pro-oncogenic chemokine. A cross-communication between the TGF-β signaling network and estrogens has been postulated, which is important for breast tumorigenesis. Here, we provide evidence that inhibition of TGF-β signaling is associated with a rapid estrogen-dependent nongenomic action. Moreover, we were able to demonstrate that estrogens disrupt the TGF-β signaling network as well as TGF-β functions in breast cancer cells via the G protein-coupled receptor 30 (GPR30). Silencing of GPR30 in MCF-7 cells completely reduced the ability of 17-β-estradiol (E2) to inhibit the TGF-β pathway. Likewise, in GPR30-deficient MDA-MB-231 breast cancer cells, E2 achieved the ability to suppress TGF-β signaling only after transfection with GPR30-encoding plasmids. It is most interesting that the antiestrogen fulvestrant (ICI 182,780), which possesses agonistic activity at the GPR30, also diminished TGF-β signaling. Further experiments attempted to characterize the molecular mechanism by which activated GPR30 inhibits the TGF-β pathway. Our results indicate that GPR30 induces the stimulation of the mitogen-activated protein kinases (MAPKs), which interferes with the activation of Smad proteins. Inhibition of MAPK activity prevented the ability of E2 from suppressing TGF-β signaling. These findings are of great clinical relevance, because down-regulation of TGF-β signaling is associated with the development of breast cancer resistance in response to antiestrogens.

In-vitro pharmacology of sarpogrelate and the enantiomers of its major metabolite: 5-HT2A receptor specificity, stereoselectivity and modulation of ritanserin-induced depression of 5-HT contractions in rat tail artery.

The new antiplatelet agent sarpogrelate (MCI‐9042), its major metabolite (R,S)‐1‐[2‐[2‐(3‐methoxyphe‐nyl)ethyl]phenoxy]‐3‐(dimethylamino)‐2‐propanol ((R,S)‐M‐1) and the enantiomers of (R,S)‐M‐1 were studied as antagonists at 5‐HT2A receptors, 5‐HT1‐like receptors, 5‐HT3 receptors, α1‐adrenoceptors, β‐adrenoceptors, histamine H1 receptors, histamine H2 receptors and muscarinic M3 receptors in various functional in‐vitro assays.

Anti-inflammatory and spasmolytic activity of extracts from Droserae herba

An ethanolic extract of Drosera madagascariensis inhibited human neutrophil elastase with an IC50 of 9.4 microg/ml. The naphthoquinones present in the extract were not responsible for this effect, but flavonoids like quercetin (IC50 0.8 microg/ml), hyperoside (IC50 0.15 microg/ml) and isoquercitrin (IC50 0.7 microg/ml) contributed to inhibition of the enzyme. In guinea-pig ileum the extract (0.5-1 mg/ml) induced a spasmolytic effect via affecting cholinergic M3 receptors and histamine H1 receptors, respectively. At contractile prostanoid receptors of guinea-pig trachea the Drosera extract was not effective.

Effects of ginger constituents on the gastrointestinal tract: role of cholinergic M3 and serotonergic 5-HT3 and 5-HT4 receptors.

The herbal drug ginger (Zingiber officinale Roscoe) may be effective for treating nausea, vomiting, and gastric hypomotility. In these conditions, cholinergic M (3) receptors and serotonergic 5-HT (3) and 5-HT (4) receptors are involved. The major chemical constituents of ginger are [6]-gingerol, [8]-gingerol, [10]-gingerol, and [6]-shogaol. We studied the interaction of [6]-gingerol, [8]-gingerol, [10]-gingerol (racemates), and [6]-shogaol with guinea pig M (3) receptors, guinea pig 5-HT (3) receptors, and rat 5-HT (4) receptors. In whole segments of guinea pig ileum (bioassay for contractile M (3) receptors), [6]-gingerol, [8]-gingerol, [10]-gingerol, and [6]-shogaol slightly but significantly depressed the maximal carbachol response at an antagonist concentration of 10 µM. In the guinea pig myenteric plexus preparation (bioassay for contractile 5-HT (3) receptors), 5-HT maximal responses were depressed by [10]-gingerol from 93 ± 3 % to 65 ± 6 % at an antagonist concentration of 3 µM and to 48 ± 3 % at an antagonist concentration of 5 µM following desensitization of 5-HT (4) receptors and blockade of 5-HT (1) and 5-HT (2) receptors. [6]-Shogaol (3 µM) induced depression to 61 ± 3 %. In rat esophageal tunica muscularis mucosae (bioassay for relaxant 5-HT (4) receptors), [6]-gingerol, [8]-gingerol, [10]-gingerol, and [6]-shogaol (2-6.3 µM) showed no agonist effects. The maximal 5-HT response remained unaffected in the presence of the compounds. It is concluded that the efficiency of ginger in reducing nausea and vomiting may be based on a weak inhibitory effect of gingerols and shogaols at M (3) and 5-HT (3) receptors. 5-HT (4) receptors, which play a role in gastroduodenal motility, appear not to be involved in the action of these compounds.

Fibrotic valvular heart disease is not related to chemical class but to biological function: 5-HT2B receptor activation plays crucial role

Companion letters have been published in this issue of Movement Disorders: Chaudhuri et al., pp 1522–1523, and Rascol et al., pp 1524–1525.

Imidazole derivatives as a novel class of hybrid compounds with inhibitory histamine N-methyltransferase potencies and histamine hH3 receptor affinities

In this study, a novel series of imidazole-containing compounds with dual properties, that is, inhibitory potency at the enzyme histamine N(tau)-methyltransferase (HMT) and antagonist potency at histamine H(3) receptors was designed and synthesized. Pharmacologically, these new hybrid drugs were evaluated in functional assays for their inhibitory potencies at rat kidney HMT and for their antagonist activities on synaptosomes of rat cerebral cortex. For selected compounds, binding affinities at recombinant human histamine H(3) receptors were determined. The first compounds (1-10) of the series proved to be H(3) receptor ligands of high potency at rat synaptosomes or of high binding affinity at human H(3) receptors, respectively, but of only moderate activity as inhibitors of rat kidney HMT. In contrast, aminoquinoline- or tetrahydroacridine-containing derivatives 11-17 also displayed HMT inhibitory potency in the nanomolar concentration range. Preliminary data from molecular modeling investigations showed that the imidazole derivative 15 and the HMT inhibitor quinacrine possess identical binding areas. The most interesting compound (14) is simultaneously a highly potent H(3) receptor ligand (K(i)=4.1nM) and a highly potent HMT inhibitor (IC(50)=24nM), which makes this derivative a valuable pharmacological tool for further development.

Evidence for 5-HT2B and 5-HT7 receptor-mediated relaxation in pulmonary arteries of weaned pigs

This study characterizes the relaxant response to 5-hydroxytryptamine (5-HT) in prostaglandin F2α (PGF2α)-precontracted pulmonary arteries of weaned pigs. In arterial rings with intact endothelium, the relaxation to 5-HT was biphasic. The high affinity component of relaxation to 5-HT (0.1–10 nM) was abolished by mechanical removal of the endothelium or after the addition of l-NAME (200 μM), and was inhibited by the 5-HT2B/2C receptor antagonist SB 206553 (1 μM), but not the 5-HT2C receptor antagonist SB 242084 (0.1 μM). Endothelium-intact arteries were also relaxed by the selective 5-HT2B receptor agonist BW 723C86 (pD2 7.7). The relaxant response to BW 723C86 was inhibited by 1 μM SB 206553 (pKB 6.8). The low affinity component of relaxation to 5-HT (≥30 nM) remained unaffected after mechanical removal of the endothelium or the addition of l-NAME. In endothelium-denuded arterial rings, 5-HT, 5-carboxamidotryptamine (5-CT), 5-methoxytryptamine (5-MeOT), and frovatriptan produced monophasic relaxations with pD2 values of 6.5, 7.5, 5.9, and 4.7 respectively. Relaxant responses to the agonists were antagonized by the selective 5-HT7 receptor antagonist SB 269970 (pKB 8.2–8.9). The relaxant response to the potent 5-HT7 receptor agonist 5-CT was also antagonized by methiothepin (pKB 9.6), pimozide (pKB 8.2), mesulergine (pKB 7.7), methysergide (pKB 7.4), clozapine (pKB 7.6), and spiperone (pKB 7.4). The estimated pKB values argue in favor of an involvement of 5-HT7 receptors in the direct vasorelaxant action of 5-HT in the pulmonary arteries of weaned pigs. The relaxant response to 5-CT was associated with an increase in cAMP that was surmountably antagonized by SB 269970 (pKB 8.6). The present in vitro bioassay can be used to characterize new drugs with potential agonist or antagonist properties at functional 5-HT7 receptors.

Development of FUB 181, a Selective Histamine H3-Receptor Antagonist of High Oral in Vivo Potency with 4-(?gv-(Arylalkyloxy)alkyl)-1H-imidazole Structure

A series of 4‐(?gv‐(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 Nτ‐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‐imidazol‐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 antagonist 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 α1, β1/2, serotonergic 5‐HT2A, 5‐HAT3, 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.

Antispasmodic activity of essential oil from Lippia dulcis Trev.

AIM OF THIS STUDY To investigate the essential oil of Lippia dulcis Trev. (Verbenaceae) that is traditionally used in the treatment of cough, colds, bronchitis, asthma, and colic in Middle America for antispasmodic activity. MATERIALS AND METHODS We used a porcine bronchial bioassay to study contractile responses to carbachol and histamine in the absence or presence of the essential oil. RESULTS The essential oil showed anti-histaminergic and anti-cholinergic activities at 100 microg/ml. CONCLUSIONS The anti-histaminergic and anti-cholinergic activities of the essential oil of Lippia dulcis support the rational use of the plant or plant extracts to treat bronchospasm.

α2-Adrenoceptors are targets for antipsychotic drugs.

RationaleAlmost all antipsychotic drugs (APDs), irrespective of whether they belong to the first-generation (e.g. haloperidol) or second-generation (e.g. clozapine), are dopamine D2 receptor antagonists. Second-generation APDs, which differ from first-generation APDs in possessing a lower propensity to induce extrapyramidal side effects, target a variety of monoamine receptors such as serotonin (5-hydroxytryptamine) receptors (e.g. 5-HT1A, 5-HT2A, 5-HT2C, 5-HT6, 5-HT7) and α1- and α2-adrenoceptors in addition to their antagonist effects at D2 receptors.ObjectiveThis short review is focussed on the potential role of α2-adrenoceptors in the antipsychotic therapy.ResultsSchizophrenia is characterised by three categories of symptoms: positive symptoms, negative symptoms and cognitive deficits. α2-Adrenoceptors are classified into three distinct subtypes in mammals, α2A, α2B and α2C. Whereas the α2B-adrenoceptor seems to play only a minor role in the brain, activation of postsynaptic α2A-adrenoceptors in the prefrontal cortex improves cognitive functions. Preclinical models such as D-amphetamine-induced locomotion, the conditioned avoidance response and the pharmacological N-methyl-d-aspartate receptor hypofunction model have shown that α2C-adrenoceptor blockade or the combination of D2 receptor antagonists with idazoxan (α2A/2C-adrenoceptor antagonist) could be useful in schizophrenia. A potential benefit of a treatment combination of first-generation APDs with the α2A/2C-adrenoceptor antagonists idazoxan or mirtazapine was also demonstrated in patients with schizophrenia.ConclusionsIt is concluded that α2-adrenoceptors may be promising targets in the antipsychotic therapy.