Biomedical subjects

J M Jansen

Publications and source records attributed to J M Jansen.

At least 19 recordsLinked to original sources

PubMed1999

A unified and quantitative receptor model for the microtubule binding of paclitaxel and epothilone.

[formula: see text] Paclitaxel and epothilone represent the two major classes of antimicrotubule agents that promote tubulin polymerization and, presumably, mitotic arrest during cell division. A common minireceptor binding site model at beta-tubulin has been constructed for these structurally divergent compounds. Utilizing 20 amino acids identified in photoaffinity labeling experiments, the 3-D model correlates measured and predicted Ki's with r = 0.99 and rms(delta Gcalc-delta Gexp) = 0.2 kcal/mol. In addition, the model predicts the affinity of compounds not used in the training set and explains much of the SAR for the paclitaxel and epothilone families.

Antineoplastic Agents↗

PubMed1999

Analysis of pulmonary microvasculature changes after photodynamic therapy delivered to distant sites.

Photodynamic therapy (PDT) can exert local damage by direct tumor cytotoxicity, by disruption of the microvasculature or by a combination of these effects. Although systemic effects after PDT of small tissue areas (< 1% total body surface area) are unlikely, treatment of larger areas may result in an accumulated effect leading to toxicity. Several investigators have described animal death after high dose PDT to tumors on the hind limb of animals and hypothesized that a toxic shock syndrome caused by vasoactive agents released after PDT is responsible. Because one of the most vulnerable organs to toxic shock injury is the lung, we studied the systemic effects of local PDT to this organ by intravital microscopy using a pulmonary window chamber. The PDT treatment conditions (25 mg/kg Photofrin, 24 h, 150 J/cm2 630 nm, maximum area 6.28 cm2) were chosen that produce systemic toxicity and lethality in rats. Adhesion of leukocytes in the lung was monitored in vivo using anti-CD-13-labeled microspheres. The progression of pulmonary edema was assessed by monitoring the leakage of rhodamine-labeled albumin and by wet-to-dry lung weight ratios. Although an increased leukocyte adherence was observed and a significant number of animals died after the extensive PDT treatment, no biologically significant lung edema could be demonstrated. These data indicate that lung edema and acute respiratory distress syndrome is not the cause of death in these animals and that the toxicity is related to other mechanisms including circulatory shock after extensive muscle damage.

Animals↗

PubMed1996

10-substituted 11-oxygenated (R)-aporphines: synthesis, pharmacology, and modeling of 5-HT1A receptor interactions.

Derivatives of the selective serotonin 5-HT1A receptor agonist (R)-11-hydroxy-10-methylaporphine (2) having various substituents in the C10-position or at the nitrogen have been synthesized from natural morphine or 6-O-acetylcodeine, respectively. The C10-substituents were introduced using efficient Stille or Suzuki cross-coupling reactions. The compounds were evaluated for their affinities to 5-HT1A and dopamine (DA) D1 and D2A receptors in vitro. All compounds tested displayed low (micromolar) affinities to D1 and D2A receptors. In addition, changes in steric bulk and/or electronic properties of the C10-substituent as compared to a C10-methyl group, as well as substitution of the N-methyl group for a hydrogen or a larger N-alkyl group, produced a marked decrease in the affinities to 5-HT1A receptors. Selected compounds that displayed moderate to high affinities to 5-HT1A receptors were evaluated for their ability to stimulate 5-HT1A receptors in vivo. The evaluated compounds behaved as agonists at 5-HT1A receptors, except for the N-propyl analogue of 2, (R)-11-hydroxy-10-methyl-N-propylnoraporphine (23), which displayed weak DA receptor agonism at the doses tested. Hence, the substitution pattern of 2 (a C10-methyl, a C11-hydroxy, and an N-methyl group) appears to be optimal for potent interaction of 10,11-disubstituted (R)-aporphines with 5-HT1A receptors. Modeling of ligand-5-HT1A receptor interactions was performed in an attempt to rationalize the observed affinity data. The binding site model suggests the presence of a "methyl pocket" in the 5-HT1A receptor binding ste. The C11-methoxy-substituted aporphines appear to have a different binding mode compared to 2, implying a different accessibility of these compounds to the "methyl pocket".

Animals↗

PubMed1996

11-substituted (R)-aporphines: synthesis, pharmacology, and modeling of D2A and 5-HT1A receptor interactions.

A series of C11-substituted (R)-aporphines and C11-oxygenated (R)-noraporphines has been synthesized and evaluated for central serotonergic and dopaminergic effects in vitro and in vivo. The various C11-substituents were introduced using efficient nickel- and palladium-catalyzed reactions of the corresponding triflate (R)-11-[[(trifluoromethyl)sulfonyl]oxy]aporphine (6). Several compounds display high affinity to serotonin 5-HT1A receptors in spite of major differences in steric bulk and electronic properties of the various C11-substituents. A change of the N-methyl group of the nonselective 3 to H [23, (R)-11-hydroxynoraporphine] or propyl [2, (R)-11-hydroxy-N-propylnoraporphine] increases the selectivity for 5-HT1A receptors (100-fold) and dopamine D2A receptors (3-fold), respectively. Compounds 3 and 23 have similar affinities to 5-HT1A receptors, whereas the propyl substituent of 2 not only enhances the selectivity for D2A receptors but also increases the D2A affinity. Modeling of ligand-receptor binding site interactions yielded an interaction site model for the 5-HT1A receptor that describes a gradual change in binding mode for C11-hydroxy, -methoxy-, and -phenyl-substituted derivatives. Hydrogen bonding is hereby gradually replaced by van der Waals interactions involving a relatively large lipophilic pocket. The derived D2A receptor model can accommodate both the N-propyl substituent of 2 and the C11-ethyl substituent of 11 [(R)-11-ethylaporphine].

Animals↗

PubMed1996

The high affinity melatonin binding site probed with conformationally restricted ligands--II. Homology modeling of the receptor.

We present the first 3-D model of the melatonin receptor based on the recently published amino acid sequence of the cloned melatonin receptor. The seven trans membrane helices were positioned using the helices found in the structure of Bacterio Rhodopsine. From the results of an indirect modeling study with six melatonergic agents, an alignment of these compounds was found directing towards common interaction points. These points are suggested to be the two serines in helix three and the histidine in helix five, forming hydrogen bonds with the amide function and the methoxy-oxygen in melatonin, respectively. The ligands were docked into these binding sites and the receptor-ligand complexes were energy minimized. Considering the position of the active and inactive ligands in the receptor and their respective occupied volumes, the structure-activity relationships are rationalized by the suggested model. This model can be of use as a pharmacological test model in molecular biological studies and as a basis to develop compounds being active as synchronizing circadian agents.

Amino Acid Sequence↗

PubMed1996

The high affinity melationin binding site probed with conformationally restricted ligand--I. Pharmacophore and minireceptor models.

The affinities of enantiomers of conformationally restricted melatonin analogues for the ML-1 and ML-2 putative melatonin receptor subtypes are reported. Most ligands exhibited reversed stereoselectivity when competing with 125I 2-iodomelatonin binding to chicken retinal (ML-1) and hamster brain (ML-2) membranes, further supporting the biochemical and pharmacological differences reported for these two sites. Based on the data for the ML-1 site and thorough conformational analyses of several ligands, two pharmacophore models were derived using the program APOLLO. The pharmacophoric elements included were putative receptor points from the amide NH, the amide CO, and the methoxy-O, together with the normal through the phenyl ring. The large drop in ML-1 affinity observed for 4-methoxy-2-acetamido-indan (6a) could not be explained from either of these models. Minireceptors were subsequently built around the two pharmacophores using Yak. Analysis of the resulting ligand-minireceptor interactions offered an explanation for the low affinity of 6a and allowed one of the pharmacophore models to be selected for use in future drug design.

Animals↗

PubMed1994

Semipreparative enantiomeric separation of a series of putative melatonin receptor agents using tri-acetylcellulose as chiral stationary phase.

In order to obtain milligram amounts of the enantiomers of a series of compounds to be tested for binding to the melatonin binding site, a system for semipreparative enantiomeric separation was set up using tri-acetylcellulose as the chiral stationary phase. Interactions of this class of compounds with tri-acetylcellulose were examined on an analytical scale with a series of 20 compounds. Apparently, both steric and electrostatic interactions determine retention behavior on tri-acetylcellulose. Semipreparative separations were carried out for a subset of seven compounds. The purity of the first eluting enantiomer usually was around 99%, whereas the purity of the second eluting enantiomer was slightly less. The system described is easy to use and has the major advantage that a series of compounds can be separated with one technique. The purities obtained are sufficient for a first screen of their affinity.

Binding Sites↗

PubMed1993

Conformational properties of melatonin and two conformationally restricted agonists: a molecular mechanics and NMR spectroscopic study.

The hormone melatonin (N-acetyl-5-methoxytryptamine) has been implicated in the regulation of several neural and endocrine processes that are cued by the daily change in photoperiod. The conformational properties of melatonin and two conformationally restricted agonists, 8-methoxy-2-acetamidotetralin and cis-1-methyl-8-methoxy-2-acetamidotetralin, were examined as a starting point for SAR studies. The conformational analysis was carried out by means of molecular mechanics calculations (MM2-85 force field) using a step-wise build-up procedure and the molecular modelling program MacroModel (which has a modified version of the MM2 force field) for Monte Carlo and systematic tree searches. NMR spectroscopy was used to evaluate the conformational behaviour in solution. The three search methods were complementary and produced a good description of the conformational characteristics. The two force fields produced different geometries of some low energy conformations and also different relative steric energies. When using the MM2-85 force field, an intra-molecular interaction between the amide-H and the aromatic system lowers the relative energies of several conformations of both melatonin and the 2-amidotetralins. However, NMR experiments indicated that these interactions, which may be quite important in vacuo, are not important in solution.

Computer Simulation↗

PubMed1991

Pharmacological profile of non-hydroxylated and ether derivatives of the potent D2-selective agonist N-0437.

Derivatives of the potent dopamine D2-selective agonist 2-(N-propyl-N-2-thienylethylamino)-5-hydroxytetralin (N-0437) were designed, aimed at producing drugs with less sensitivity towards metabolic inactivation (in particular glucuronidation at the 5-OH position). Since aminotetralins with a 5-methoxy substituent or lacking the 5-hydroxy group have been reported to retain dopaminergic activity, the non-5-hydroxylated N-0437 (N-0918) and two ethers of N-0437 [5-methoxy-N-0437 (N-0724) and 5-cyclopentoxy-N-0437 (N-0953)] have been prepared and tested. Three indices for activity at central dopamine receptors are considered: (1) the displacement of (3H)-SCH-23390 and (3H)-spiperone from calf caudate membranes, (2) the effects on dopamine release and metabolism in the striatum of freely moving rats after systemic and intrastriatal administration as assessed by brain microdialysis, and (3) the ability to elicit contralateral turning in rats with a unilateral 6-OH-dopamine lesion of the nigrostriatal pathway. In order to differentiate between direct dopaminergic activity and metabolic activation, brain and plasma levels of N-0437 after administration of N-0724 and N-0953 were measured. The results show the necessity of the 5-OH group for direct dopaminergic activity: N-0918, N-0724 and N-0953 are all inactive after intrastriatal administration in the microdialysis model and all three drugs show a weak in vitro affinity for both D1 and D2 receptors. Although N-0918 is also inactive after systemic administration in the microdialysis and turning model, N-0724 and N-0953 do exhibit dopaminergic activity after systemic administration in these models.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1987

Double-blind multicentre comparison of omeprazole and ranitidine in the treatment of reflux oesophagitis.

Omeprazole 60 mg once daily was compared with ranitidine 150 mg twice daily in an endoscopically-controlled, double-blind randomised trial in 51 outpatients with erosive or ulcerative reflux oesophagitis (grade 2 or 3). Endoscopy was repeated after 4 weeks and, in the absence of healing, again after 8 weeks. Symptoms were assessed before entry and after 2, 4, and 8 weeks. Patients who were unhealed after 8 weeks were blindly switched to the other drug and treatment was continued for another 4 to 8 weeks. The healing rate (change to grade 0 or 1 oesophagitis) after 4 weeks was 19 of 25 patients treated with omeprazole and 7 of 26 patients treated with ranitidine (p = 0.002). The corresponding figures after 8 weeks were 22 of 25 and 10 of 26 (p = 0.001). The higher healing rate with omeprazole was reflected in a significantly faster and stronger improvement of reflux symptoms. 13 patients, who were unhealed after 8 weeks on ranitidine, were healed after switching treatment. Healing was achieved in 1 of 3 patients who were switched to ranitidine. There were no adverse events or changes in laboratory variables of clinical importance. Omeprazole is superior to ranitidine in the short-term treatment of reflux oesophagitis.

Clinical Trials as Topic↗

PubMed1987

Omeprazole in peptic ulcers resistant to histamine H2-receptor antagonists.

Eighteen patients with duodenal, gastric or jejunal ulcers, resistant to at least 3 months treatment with histamine H2-receptor antagonists, singly or in combination with other anti-ulcer drugs, were treated with 40 mg omeprazole once daily for up to 8 weeks. All ulcers healed, the majority within two weeks. After ulcer healing patients were given maintenance therapy with high doses of cimetidine or ranitidine. Of 15 patients on maintenance therapy with H2-receptor antagonists, 12 (80%) developed a relapse after a period ranging from 3 to 52 weeks. Two patients were lost to follow-up. After re-healing on 40 mg omeprazole, two patients were given 20 mg omeprazole daily as maintenance therapy but relapses occurred again after 14 and 26 weeks respectively. After re-healing on 40 mg omeprazole, these two patients and one additional patient received maintenance therapy with 40 mg omeprazole daily. At present these three patients have been relapse-free for periods varying from 16 to 52 weeks. No side effects were registered during treatment with omeprazole. It is therefore concluded that omeprazole is highly effective in healing refractory peptic ulcers and that omeprazole maintenance therapy may be useful for prevention of relapse. Patients are sometimes seen with peptic ulceration which appears resistant to therapy with histamine H2-receptor antagonists, colloidal bismuth subcitrate, sucralfate or pirenzepine, either given as monotherapy for a prolonged period of time or as combination therapy. Usually the reason for such therapeutic failure remains obscure. Whether virtually total abolition of acid secretion will allow ulcer healing in these circumstances is unknown.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1984

Effect of oral omeprazole on serum gastrin and serum pepsinogen I levels.

Fasting and meal-stimulated serum gastrin and serum pepsinogen I levels were determined in 8 healthy volunteers before, during, and after administration of 30 mg of omeprazole daily for 14 days. Fasting levels and the integrated increment of serum gastrin were significantly increased after 7 and 14 days of treatment with omeprazole, but not after a single dose. Fasting levels measured 2, 4, 7, 14, and 21 days after stopping treatment with omeprazole and the integrated increment of serum gastrin determined 7 and 14 days after discontinuation of omeprazole were not significantly different from pretreatment levels. Fasting serum pepsinogen I levels increased progressively during omeprazole treatment. This increase was significant after 7 and 14 days of treatment and 2 and 4 days after discontinuing omeprazole. These levels were not significantly different from pretreatment levels 7, 14, and 21 days after omeprazole treatment. Serum pepsinogen I did not significantly change after the test meal. It is concluded that fasting and meal-stimulated serum gastrin levels and fasting serum pepsinogen I levels increase significantly during treatment with 30 mg of omeprazole daily for 14 days, but after stopping treatment there is a rapid return to pretreatment levels.

Adult↗

PubMed1980

Usefulness of forced expiration slope ratios for detecting mild airway abnormalities.

To assess their value for early recognition of airway abnormalities, forced expiration slope ratios as recently defined by Mead, were measured at 5 lung volumes in 114 healthy nonsmokers and in 76 cigarette smokers. In healthy nonsmokers, slope ratios were independent of sex and body height, but were significantly correlated with age. They tended to be higher at low lung volume, particularly in older subjects. In male smokers with a tobacco consumption of less than 5 pack-years, slope ratios were increased at both ends of the volume range, suggesting nonhomogeneous lung emptying and peripheral airway obstruction. With increasing tobacco consumption, slope ratios tended to return to normal values at low lung volume, perhaps because of airway closure. In female smokers, slope ratios were decreased at high lung volume and increased at low lung volume, suggesting that both central and peripheral airways were abnormal. Mead's analysis appeared to be a useful tool for discussing the data in terms of functional abnormalities. However, because of their large variability, slope ratios were not as successful as transit time indices for recognizing abnormal subjects.

Adult↗

PubMed1973

Antithrombin-3 deficiency in a Dutch family.

A Dutch family (family A) with inherited antithrombin-III deficiency and an increased incidence of venous thrombosis was investigated. Antithrombin-III levels were measured by means of a coagulation assay in plasma and by single radial immunodiffusion in plasma and serum.THREE GROUPS COULD BE DISTINGUISHED: group I comprised the relations-in-law of family A, group II the members of family A with a plasma antithrombin-III level higher than 90% of normal, when determined by the immunoassay, and group III the members of family A with an antithrombin-III level of less than 60%. To group III belonged all eight adults with an abnormal tendency to thrombosis, and furthermore nine children, all having a parent with abnormally low antithrombin-III levels. Mean plasma and serum antithrombin-III levels were significantly decreased in group III. However, the results of the coagulation assay showed some overlap between groups II and III. In addition, the immunoassay appeared to be much less laborious than the coagulation assay. Therefore, the former assay is recommended in any search for similar families. The results of our family investigation confirm the findings of Egeberg (1965) that inherited antithrombin-III deficiency, giving rise to plasma levels between 50 and 60% of normal, causes thrombophilia and that the pattern of inheritance is autosomal dominant.

Adult↗

PubMed1972