Biomedical subjects

A Schuster

Publications and source records attributed to A Schuster.

At least 37 records · Page 2Linked to original sources

PubMed2001

Cytosolic-free calcium in smooth-muscle and endothelial cells in an intact arterial wall from rat mesenteric artery in vitro.

The regulation of cytosolic-free calcium concentration of smooth-muscle and endothelial cells was mainly studied on cultured cells where the cross talk between these two coupled cell types is lost. In the present study, the cytosolic-free calcium concentration in the endothelial and the smooth-muscle cells was examined in an intact arterial wall in vitro. Strips of the main branch of rat mesenteric artery were used. Cytosolic-free calcium concentration [Ca2+]i was estimated by determining the fluorescence ratio of the two calcium probes, Fluo-4 and Fura red. The emitted fluorescence of both probes was measured with a confocal microscope. We showed that potassium and phenylephrine, which increase the cytosolic -free calcium concentration of the smooth-muscle cells, also indirectly influence the calcium concentration in the endothelial cells. By simultaneously determining [Ca2+]i in the endothelial and the smooth-muscle cells of an arterial strip, we observed that when calcium increases in the endothelial cells in response to acetylcholine, it slightly decreases in the smooth-muscle cells. We conclude that the regulation of [Ca2+]i in the arterial endothelial cell, depends according to the stimuli either upon the endothelial cells themselves, or upon the coupled smooth-muscle cells.

Acetylcholine↗

PubMed2001

Montelukast added to budesonide in children with persistent asthma: a randomized, double-blind, crossover study.

OBJECTIVE: We tested the hypothesis that adding montelukast to budesonide would improve asthma control in children with inhaled glucocorticoid-dependent persistent asthma. STUDY DESIGN: In a multicenter, randomized, double-blind, crossover study, we compared the benefit of adding montelukast, 5 mg, or placebo once daily to budesonide, 200 microg, twice daily. RESULTS: After a 1-month run-in with budesonide, 200 microg, twice daily, 279 children were randomized to montelukast or placebo. The mean +/- SD age was 10.4 +/- 2.2 years, the mean forced expiratory volume in 1 second (FEV(1)) was 77.7% +/- 10.6% predicted, and reversibility was 18.1% +/- 12.9%. Compared with adding placebo to budesonide, adding montelukast produced significant improvements in mean percent change from baseline FEV(1) (P =.062 [P =.010 for per-protocol analysis]), mean absolute change from baseline FEV(1) (P =.040), mean increase from baseline in morning (P =.023) and evening (P =.012) peak expiratory flows, decrease in exacerbation days by approximately 23% (P <.001), decreased beta2-agonist use (P =.013), and reduced blood eosinophil counts (P <.001). The treatments did not differ significantly with regard to safety. CONCLUSIONS: Montelukast, 5 mg, added to budesonide improved asthma control significantly, indicated by a small additive effect on lung function and a clinically relevant decrease in asthma exacerbation days.

Acetates↗

PubMed2001

Simultaneous arterial calcium dynamics and diameter measurements: application to myoendothelial communication.

The goal of the present study was to analyze the intercellular calcium communication between smooth muscle cells (SMCs) and endothelial cells (ECs) by simultaneously monitoring artery diameter and intracellular calcium concentration in a rat mesenteric arterial segment in vitro under physiological pressure (50 mmHg) and flow (50 microl/min) in a specially developed system. Intracellular calcium was expressed as the fura 2 ratio. The diameter was measured using a digital image acquisition system. Stimulation of SMCs with the alpha(1)-agonist phenylephrine (PE) caused not only an increase in the free intracellular calcium concentration of the SMCs as expected but also in the ECs, suggesting a calcium flux from the SMCs to the ECs. The gap junction uncoupler palmitoleic acid greatly reduced this increase in calcium in the ECs on stimulation of the SMCs with PE. This indicates that the signaling pathway passes through the gap junctions. Similarly, although vasomotion originates in the SMCs, calcium oscillates in both SMCs and ECs during vasomotion, suggesting again a calcium flux from the SMCs to the ECs.

Animals↗

PubMed2001

Role of smooth muscle cells on endothelial cell cytosolic free calcium in porcine coronary arteries.

We tested the hypothesis that the cytosolic free calcium concentration in endothelial cells is under the influence of the smooth muscle cells in the coronary circulation. In the left descending branch of porcine coronary arteries, cytosolic free calcium concentration ([Ca(2+)](i)) was estimated by determining the fluorescence ratio of two calcium probes, fluo 4 and fura red, in smooth muscle and endothelial cells using confocal microscopy. Acetylcholine and potassium, which act directly on smooth muscle cells to increase [Ca(2+)](i), were found to indirectly elevate [Ca(2+)](i) in endothelial cells; in primary cultures of endothelial cells, neither stimulus affected [Ca(2+)](i), yet substance P increased the fluorescence ratio twofold. In response to acetylcholine and potassium, isometric tension developed by arterial strips with intact endothelium was attenuated by up to 22% (P < 0.05) compared with strips without endothelium. These findings suggest that stimuli that increase smooth muscle [Ca(2+)](i) can indirectly influence endothelial cell function in porcine coronary arteries. Such a pathway for negative feedback can moderate vasoconstriction and diminish the potential for vasospasm in the coronary circulation.

Acetylcholine↗

PubMed2001

Antileukotrienes in asthma: present situation.

Leukotrienes are key mediators in asthma. Over the last 5 years, several antileukotrienes, including three receptor antagonists (montelukast, pranlukast and zafirlukast) and one 5-lipoxygenase inhibitor (zileuton), have been marketed and, to date, this class of drugs is being used widely. Still, their definite place in the asthma treatment algorithm is not yet established. These novel drugs have not yet all been evaluated in the same depth, but they have all been shown to possess anti-inflammatory properties and to be effective in chronic asthma treatment. Zafirlukast and montelukast are particularly efficacious in exercise-induced asthma and zileuton appears valuable for treating aspirin-intolerant asthmatics. Clinical comparisons to other anti-asthma drugs are still sparse. The corticosteroid-sparing effect of antileukotrienes is fairly well established except for zileuton, even though this drug has been evaluated most thoroughly in terms of its anti-inflammatory effects. Montelukast is the antileukotriene most extensively evaluated in children and zafirlukast has recently been approved for use in children in the USA, although not yet in Europe. Therapeutic regimes are quite variable depending on the drug, but all of the antileukotrienes marketed to date are taken orally; hence, compliance is usually greater than that with inhaled medication. Response to antileukotrienes appears to depend on the individual patients' characteristics, in particular on genetic polymorphisms related to leukotriene metabolism. All drugs of this class are well tolerated and only in the case of zileuton is there potential for hepatic adverse effects. The diagnosis of Churg-Strauss syndrome made among patients taking antileukotrienes seems to be more related to the withdrawal of corticosteroids than to the antileukotrienes themselves.

Acetates↗

PubMed2000

Liquid chromatography/electrospray tandem mass spectrometry method for the quantitation of fosinoprilat in human serum using automated 96-well solid-phase extraction for sample preparation.

A sensitive, specific, accurate and reproducible liquid chromatography/electrospray tandem mass spectrometry method was developed and validated for the quantitation of fosinoprilat in 0.2 mL of human serum. The method employed acidification (with pH 4.0 sodium acetate buffer) of the serum samples to minimize the hydrolysis of the prodrug fosinopril to fosinoprilat prior to purification by automated 96-well solid-phase extraction. The required chromatographic separation of fosinoprilat and fosinopril was achieved isocratically on a Luna C8 analytical column (2 x 50 mm, 3 microm). The total run time was 2 min. The mobile phase contained methanol and water with 10 mM ammonium acetate. Detection was by positive ion electrospray tandem mass spectrometry. The standard curve, which ranged from 2.00 to 500 ng/mL, was fitted to a 1/x(2) weighted linear regression model. Fosinoprilat quality control (QC) samples used to determine the accuracy and precision of the method were prepared in human serum at concentrations of 5.00, 200, 400 and 1000 ng/mL. The assay accuracy was within 8% (dev). The intra- and inter-assay precisions were within 6 and 3% (RSD), respectively. Fosinopril QC samples used to gauge the rate of hydrolysis of fosinopril to fosinoprilat during the assay procedure were prepared in human serum at 500 ng/mL. The hydrolysis of fosinopril to fosinoprilat was </=1%. This degree of conversion would cause little error in the analysis of post-dose serum samples since such samples are known to contain low levels of the prodrug compared with the drug.

Analysis of Variance↗

PubMed2000

[Effect of glass ceramics on bone regeneration in calvarial defects. Experimental study].

INTRODUCTION: The purpose of this study was to investigate the influence of different compositions of resorbable porous glass ceramics on their performance in calvarial defects. MATERIAL AND METHODS: Full-thickness defects (8.1 mm diameter) were made in the calvaria of 75 adult Sprague-Dawley rats. Pellets of porous glass ceramics were inserted press-fit into 60 defects. Four different materials were implanted into each of 15 animals: (1) glass ceramic with a high relation of calcium to phosphate containing silicate; (2) glass ceramic with a high relation of calcium to phosphate without silicate; (3) glass ceramic with a low relation of calcium to phosphate without silicate; and (4) glass ceramic with a low relation of calcium to phosphate containing silicate. Five implants of each group were evaluated by fluorescence microscopy and light microscopy after 6, 13, and 26 weeks. RESULTS: Those glass ceramics with a high relation of calcium to phosphate showed formation of new bone entering the defect from the margins as soon as 6 weeks postoperatively. After 26 weeks, the formation of new bone reached the center of the defect. In the other glass ceramics, the formation of unmineralized osteoid was visible entering the defect from the margins. No mineralization was seen 26 weeks postoperatively. There was no significant difference between glass ceramics containing silicate and those free of silicate. CONCLUSIONS: Bioresorbable glass ceramics may be of benefit in the treatment of osseous defects without functional loading.

Animals↗

PubMed2000

ENVIRONMENTAL AUDITING: Environmental Auditing in Hospitals: First Results in a University Hospital.

/ While medical audit in infection control today is one important element in the quality assurance of health care, environmental auditing, approved in 1993 by the Council of the European Communities for the industrial sector, so far has not been used as a tool to control and reduce environmental pollution caused by medical care. The aim of this study was to investigate whether environmental auditing according to the European Eco-Management and Audit Scheme (EMAS) can be implemented in hospitals as a process of improvement in protection of the environment. In a prior publication the methodological issues and the organizational steps that had to be taken were described. An environmental review of the activities of the Freiburg University Hospital and an ecoanalysis of the input and output were performed. The results of this analysis, published in an environmental report, provide a fundamental data set for the consumption of energy, water, materials, and the burdens of major pollutants and waste. Regarding the organizational structure of the hospital, the first steps towards an integrating environmental management system as demanded by EMAS could be taken. Beside supporting advantages, e.g., improvement of environmental safety, public image and staff contentment, and potential economic benefits such as less cost to be paid for energy and water consumption, there are important restrictions of environmental auditing in hospitals. Examples are the lack of basic environmental data, staff motivation (especially of physicians), cooperation of the organizational substructures, and funds for prefinancing urgently needed improvements in ecology. Based on the study findings, a textbook on environmental auditing in hospitals, including checklists covering all important environmental objectives, has been published to support hospitals in their efforts to achieve an optimized and sustainable practice of providing health care.

Journal Article↗

PubMed2000

Relapsing polychondritis in childhood--case report and short review.

Relapsing polychondritis (RP) is a disease of unknown etiology and it is characterized by inflammation of the cartilage. While the clinical picture of RP in adults is well described, RP in childhood is poorly documented. We describe a young girl presenting with acute dyspnea, stridor and polyarthritis. The diagnosis of RP was made 2 years after first presentation, when auricular chondritis occurred. Based on a MEDLINE search, reports on RP in childhood were reviewed. The frequency of chondritis and systemic manifestations of RP in children was compared to data in adults and found to be very similar. RP in childhood can be a life-threatening and debilitating disease.

Adult↗

PubMed2000

Anti-neutrophil cytoplasmic antibodies directed against the bactericidal/permeability-increasing protein (BPI) in pediatric cystic fibrosis patients do not recognize N-terminal regions important for the anti-microbial and lipopolysaccharide-binding activity of BPI.

This study was performed to examine the prevalence and clinical correlates of bactericidal/permeability-increasing protein anti-neutrophil cytoplasmic antibodies (BPI-ANCA) in pediatric cystic fibrosis (CF) patients and to elucidate their possible role in CF pulmonary pathology. Sera of 27 CF patients were tested for ANCA by indirect immunofluorescence (IFT) and by enzyme-linked immunosorbent assay (ELISA) for ANCA sub-specificities. BPI-ANCA were examined by using standard ELISA for BPI, lipopolysaccharide-binding protein (LBP), and BPI/LBP fusion proteins to epitope map the main binding sites and look for cross-reactivity with LBP. Pulmonary function and serum concentrations of total immunoglobulin G (IgG) were measured and infections were diagnosed. In addition, release of reactive oxygen species (ROS) by neutrophil granulocytes was measured after stimulation with monoclonal BPI-ANCA. Using IFT, two patients showed atypical ANCA staining, six patients exhibited perinuclear ANCA staining, and no cytoplasmic ANCA staining was detected. Of 27 patients, 13 (48%) were BPI-ANCA (IgG) positive, and three were also immunoglobulin A (IgA) BPI-ANCA positive; one patient had ANCA against lactoferrin; and no proteinase 3 ANCA was detected in any of the patients. All BPI-ANCA bound to the C-terminal region of the molecule; none bound to the N-terminus or to LBP. There was no significant correlation between clinical data and the occurrence of BPI-ANCA in this cross-sectional study. Release of ROS from granulocytes was induced by monoclonal BPI-ANCA. Activation of neutrophils and possible modulation of BPI-mediated opsonophagocytosis and disposal of Gram-negative bacteria and lipopolysaccharides by BPI-ANCA raise the possibility that they contribute to pulmonary pathology in pediatric CF patients but intervention longitudinal studies in large groups of patients are needed to establish a causative association.

Adolescent↗

PubMed2000

Detection of the ETV6-NTRK3 chimeric RNA of infantile fibrosarcoma/cellular congenital mesoblastic nephroma in paraffin-embedded tissue: application to challenging pediatric renal stromal tumors.

We report the development of a reverse transcriptase polymerase chain reaction assay that reliably detects the ETV6-NTRK3 chimeric RNA characteristic of infantile fibrosarcoma and the cellular variant of congenital mesoblastic nephroma (CMN) in formalin-fixed, paraffin-embedded tissue blocks. The 188 base pair polymerase chain reaction fusion product was detected in 11 of 12 cases of cellular CMN from which a larger sized control RNA band could be amplified, and even in 7 of 8 cases in which the control band was not detectable. A variety of other tumors that are in the histologic differential diagnosis of cellular CMN yielded negative results, including four classic CMNs, four rhabdoid tumors of the kidney, and four clear cell sarcomas of the kidney, confirming the assay's specificity. We further demonstrate the assay's utility by illustrating two cases of molecularly confirmed cellular CMN that mimicked rhabdoid tumor and clear cell sarcoma of the kidney. In contrast to previous reports, five mixed CMNs that had both classic and cellular areas all lacked the ETV6-NTRK3 fusion transcript. These results suggest that cases morphologically defined as mixed CMN may represent a mixed group of genetically distinct entities.

Artificial Gene Fusion↗

PubMed2000

[Multi-sequential arterial chemoembolization of advanced hepatocellular carcinomas: computerized tomography follow-up parameters for evaluating effectiveness of therapy].

PURPOSE: An evaluation of clinical and computed tomography parameters for the transarterial chemoembolization (TACE) of hepatocellular carcinoma (HCC). MATERIAL AND METHODS: Retro- and prospective analysis of 123 TACE procedures in 37 patients (mean age: 63.3 years). RESULTS: Overall mean survival rate for all treated patients was 785 days with a mean value of 387 days. The 1 year survival rate was 62%. Quantitative tumor volumetry revealed a significant difference in survival rate with a mean value of 678 days for patients with a reduction of tumor volume between 0 and 50%, 976 days for a volume reduction of 51-100% and 277 days for an increase in tumor volume during therapy. Patients with a high lipiodol retention presented improved survival data (902 days) versus patients with a low lipiodol retention (513 days). Homogeneous retention of lipiodol was a positive factor on survival as compared to an inhomogenous form of retention. CONCLUSION: In patients with a positive therapy response after TACE the prognosis can be improved by repeated embolization.

Aged↗

PubMed2000

Transarterial chemoembolization for hepatocellular carcinoma: volumetric and morphologic CT criteria for assessment of prognosis and therapeutic success-results from a liver transplantation center.

PURPOSE: To evaluate the prognostic value of volumetric computed tomography (CT) for therapy control in patients treated with repeated transarterial chemoembolization (TACE) for hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Eighty-five patients with histologically proved HCC underwent 182 TACE procedures with 50 mg/m(2) doxorubicin hydrochloride, 50 mg/m(2) cisplatin, 10 mL/m(2) iodized oil, and amilomer microspheres. The volumes of liver and tumor were measured with a region-of-interest CT technique. Iodized oil retention was estimated with CT performed 24-48 hours after treatment. RESULTS: Tumor volume expressed as a percentage of liver volume was less than 5% in 26, less than 15% in 33, and 15% or greater in 26 patients. The overall 1-year survival rate was 57.6% (mean, 534 days; median, 428 days). There was a statistically significant prolongation of survival when the tumor volume was less than 200 mL (P <.02) and less than 5% of the liver volume (P <.01). Complete (>/=75%) and good (50%-74%) iodized oil retention raised the median survival significantly (P <.001 and P <.07, respectively). Significantly reduced survival correlated with diffuse tumor growth pattern (P <.05) and presence of more than nine lesions (P <.03). CONCLUSION: TACE resulted in significant prolongation of survival in patients with tumor volumes of less than 200 mL, tumor-to-liver volume ratios of less than 5%, and iodized oil retention greater than or equal to 75%.

Adult↗

PubMed2000

A nationwide survey in Germany on fatal asthma and near-fatal asthma in children: different entities?

In adults fatal and near-fatal asthma have similar clinical characteristics. Therefore, near-fatal asthma in adults can be used as a model for fatal asthma. A nationwide study on fatal and near-fatal asthma in children <16 yrs was performed in order to assess whether, as in adults, near-fatal asthma can be used as a model for fatal asthma. From 1996 to 1998, all paediatric hospitals and paediatric pulmonologists in Germany were asked to report cases of fatal asthma and near-fatal asthma to a central survey unit (Erhebungseinheit für seltene pädiatrische Erkrankungen in Deutschland (ESPED)) on a monthly basis. All reports were followed by detailed questionnaires. Sixteen fatal and 45 near-fatal asthma cases were analysed. Fatal asthma patients were older than near-fatal asthma patients. Respiratory tract infections were frequently reported only in near-fatal asthma (47 versus 0%). The proportion of cases with rapid-type onset (duration of symptoms < or =1 h) was higher in fatal asthma (53 versus 14%). Long-term regular treatment with short acting beta2-agonists was common in both groups, but the use of concomitant inhaled corticosteroids was significantly lower in fatal asthma cases. A high proportion of poor compliance was observed in both groups. As fatal and near-fatal asthma differ significantly in important clinical aspects, analysis of near-fatal asthma might be of limited value in elucidating the causes of fatal asthma in children.

Administration, Inhalation↗

PubMed1999

New perspectives for asthma treatment: anti-leukotriene drugs.

Leukotrienes are synthesized by different cells, including eosinophils, neutrophils, basophils, lymphocytes, macrophages, and mast cells. Cysteinyl leukotrienes (LTC4, LTD4, and LTE4) are the most important leukotrienes in the pathogenesis of asthma. Pharmacologically, there are two different ways of blocking the action of leukotrienes: inhibiting their production by blocking 5-lipoxygenase or its activating protein, 5-lipoxygenase-activating protein (FLAP), (inhibitors) or by blocking their receptors (antagonists). The available antagonists are, for the moment, directed against the one receptor demonstrated to play a role in asthma symptoms, CysLT1, and they act in a competitive way. The only marketed 5-lipoxygenase inhibitor is zileuton (Zyflo). CysLT1 antagonists, currently on the pharmaceutical market in some countries, are zafirlukast (Accolate), pranlukast (Ultair, Onon), and montelukast (Singulair). Undoubtedly, drugs acting on leukotrienes constitute a new pharmacologic class in the therapeutic armamentarium for the management of asthma. From the pediatric point of view, montelukast is currently the most interesting drug of the group to date because of published trials in patients as young as 6 yr of age. At present, zafirlukast is only approved for use in patients 12 yr of age and older, although we understand that applications are likely to extend the age range into childhood shortly. However, more experience is necessary to establish a definite place for both leukotrienes in the step-by-step asthma treatment. New comparative studies (with sodium cromoglycate and inhaled steroids), which will probably be published in the near future, as well as studies on the use of montelukast in the treatment of children under 6 yr of age will add crucial information to our knowledge, and help to identify an appropriate use in the therapeutic algorithm. Montelukast will not be a substitute for inhaled corticosteroids or beta-agonists, although it may act as a 'sparing drug' (which might help tapering of steroids in some instances). Its role in exercise-induced asthma seems promising. Although its more widespread use could highlight low-frequency adverse effects, its apparent excellent tolerability is an additional advantage for the drug. Patients' preference for a twice-daily dosage over the inhaled medication, resulting in a better compliance, is relatively well established, at least for zafirlukast in adults, and these findings can probably be extended to montelukast, which only requires once-daily dosing in children.

Anti-Asthmatic Agents↗

PubMed1999

Proteinase 3, a potent secretagogue in airways, is present in cystic fibrosis sputum.

We evaluated the roles of proteinase 3 (PR3) and human neutrophil elastase (HNE), two neutrophil serine proteinases in the mechanisms leading to airway inflammation and hypersecretion in cystic fibrosis (CF). Using specific enzyme-linked immunosorbent assay (ELISA), we found higher levels of PR3 than HNE in sputum from CF patients. Using two inhibitors, ICI (Imperial Chemical Industries) 200,355 (which inhibits both HNE and PR3) and secretory leukoproteinase inhibitor (SLPI) (which inhibits only HNE), we showed that PR3 was enzymatically active in sputum, and its activity, as assessed by SLPI-resistant serine proteinase activity, correlated highly with its antigenic concentration measured by ELISA. Interestingly, sputum pellet-associated serine proteinase activity was mostly due to HNE. PR3 purified from neutrophil azurophil granules triggered airway gland secretion, as measured by the release of radiolabeled molecules from cultured bovine tracheal serous cells pulse-labeled with Na235SO4. This secretory activity was inhibited by ICI 200,355. PR3 concentration in CF sputum was highly correlated with taurine concentration, a reliable marker of airway inflammation and respiratory scores (e.g., FEV1%), whereas no significant correlation was observed with HNE. We verified that Pseudomonas aeruginosa proteinases did not interfere with the assessment of PR3 and HNE. Indeed, the PR3/HNE ratio was greatest in patients chronically infected by P. aeruginosa. We suggest that PR3 may play a role in the hypersecretory process that is characteristic of CF.

Adolescent↗

PubMed1998

The human WD repeat protein WAIT-1 specifically interacts with the cytoplasmic tails of beta7-integrins.

Integrins of the beta7 subfamily, alpha4 beta7 and alphaE beta7, contribute to lymphocyte homing and to the development of protective or autoreactive immune responses at mucosal sites. The beta subunits of integrins are considered important for regulation of stimulated cell adhesion and adhesion-dependent signal transduction. Using a yeast interaction trap screen, a human WD repeat protein, termed WAIT-1, was isolated that interacts with the integrin beta7 cytoplasmic tail and is homologous to mouse EED and Drosophila ESC proteins. WAIT-1 also binds to the cytoplasmic domains of alpha4 and alphaE but not to those of integrin beta1, beta2, and alphaL subunits. Association of WAIT-1 and beta7-integrin was confirmed by coprecipitation from transiently transfected 293 cells. The binding site for WAIT-1 was mapped to a short membrane-proximal region of the beta7 cytoplasmic tail with Tyr-735 being of critical importance. Northern blot analysis revealed multiple WAIT-1-related transcripts with differential expression in circulating leukocytes, tissue-resident cells of diverse origin, and lymphoid malignancies. These results suggest that WAIT-1, together with the recently identified RACK1, may define a novel subfamily of WD repeat proteins that interact with distinct subsets of integrin cytoplasmic tails and may act as specific regulators of integrin function.

Amino Acid Sequence↗

PubMed1998

NPY Y1 antagonists: structure-activity relationships of arginine derivatives and hybrid compounds with arpromidine-like partial structures.

Previously, omega-guanidino- and omega-aminoalkanamides, structurally derived from arpromidine-like histamine H2 receptor agonists, were reported as novel neuropeptide Y Y1 antagonists. Regardless of the backbone, they resemble BIBP 3226, an argininamide with high NPY Y1 receptor affinity and selectivity, with respect to nature and arrangement of the 'terminal' diaryl, guanidine, and hydroxyphenyl groups. Hybrid compounds were synthesized combining the argininamide backbone of BIBP 3226 or partial structures derived from the C-terminal dipeptide of NPY with characteristic substructures of arpromidine- or amide-type NPY antagonists. Additionally, some analogs of BIBP 3226 with reduced flexibility were prepared. Structure-activity relationships indicate that, in contrast to alkanamides, homologs and/or isomers of BIBP 3226 with vicinal arrangement of the phenyl rings have decreased Y1 antagonistic activity (Ca2+-assay in HEL cells). Replacement of the hydroxybenzyl group by an imidazole ring further decreases activity. It is concluded that the binding sites of NPY antagonists with one and with two basic groups are not identical. Analogs with a rigid tetrahydro-2-benzazepine or an indan group in place of the benzyl moiety in BIBP 3226 are active, indicating the role of the OH group and supporting the model proposed for the interaction of BIBP 3226 with the Y1 receptor.

Arginine↗