Sigurd Elz

Universität Regensburg, Ratisbon, Bavaria, Germany

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Publications (103)215.07 Total impact

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    ABSTRACT: A series of new piperidinomethylphenoxypropylamine-type histamine H2 receptor (H2R) antagonists with different substituted “urea equivalents” was synthesized and characterized in functional in vitro assays. Based on these data as selection criteria, radiosynthesis of N-[6-(3,4-dioxo-2-{3-[3-(piperidin-1-ylmethyl)phenoxy]propylamino}cyclobut-1-enylamino)hexyl]-(2,3-3H2)propionic amide ([3H]UR-DE257) was performed. The radioligand (specific activity: 63 Ci mmol−1) had high affinity for human, rat, and guinea pig H2R (hH2R, Sf9 cells: Kd, saturation binding: 31 nM, kinetic studies: 20 nM). UR-DE257 revealed high H2R selectivity on membranes of Sf9 cells, expressing the respective hHxR subtype (Ki values: hH1R: >10 000 nM, hH2R: 28 nM, hH3R: 3800 nM, hH4R: >10 000 nM). In spite of insurmountable antagonism, probably due to rebinding of [3H]UR-DE257 to the H2R (extended residence time), the title compound proved to be a valuable pharmacological tool for the determination of H2R affinities in competition binding assays.
    ChemMedChem 10/2014; · 2.84 Impact Factor
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    ABSTRACT: In the search for potential bioisosteres of the 4-imidazolyl ring in acylguanidines (e.g. UR-AK24), known to possess affinity to several histamine receptor subtypes (HxR, x = 1-4), and cyanoguanidine-type H4R agonists (e.g. UR-PI376), the contribution of various heterocycles to agonism, antagonism and HR subtype selectivity was studied (recombinant human H1,2,3,4Rs, isolated guinea pig organs (H1R, H2R)). While minor structural modifications of UR-PI376 analogues were not tolerated regarding H4R agonism, in the case of the acylguanidines, a 1,2,4-triazole ring shifted the selectivity toward the H2R.
    Medicinal Chemistry Communication 01/2014; 5(1):72-81. · 2.72 Impact Factor
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    ABSTRACT: Astemizole, a H1R antagonist shows high affinity to the histamine H1 receptor but only a moderate affinity to the histamine H4 receptor. This study aims to modify the astemizole to keep high affinity to the histamine H1 receptor and to increase affinity to the histamine H4 receptor. Therefore, 13 astemizole-derived compounds and astemizole-JNJ7777120-derived hybrid compounds were synthesized and pharmacologically characterized at the histamine H1 and H4 receptors. The new compounds show affinity to the histamine H1 receptor in the pK i range from 5.3 to 8.8, whereas the affinity of these compounds to the histamine H4 receptor was surprisingly rather low (pK i from 4.4 to 5.6). Three representative compounds were docked into the histamine H1 receptor and molecular dynamic studies were performed to explain the binding mode and the experimental results on a molecular level. Furthermore, taking into account the binding mode of compounds with high affinity to the histamine H4 receptor, a H1/H4-pharmacophore hypothesis was developed.
    Archiv für Experimentelle Pathologie und Pharmakologie 11/2013; · 2.15 Impact Factor
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    ABSTRACT: Premedication with a combination of histamine H1 receptor (H1R) and H2 receptor (H2R) antagonists has been suggested as a prophylactic principle, for instance, in anaesthesia and surgery. Aiming at pharmacological hybrids combining H1R and H2R antagonistic activity, a series of cyanoguanidines 14-35 was synthesized by linking mepyramine-type H1R antagonist substructures with roxatidine-, tiotidine-, or ranitidine-type H2R antagonist moieties. N-desmethylmepyramine was connected via a poly-methylene spacer to a cyanoguanidine group as the "urea equivalent" of the H2R antagonist moiety. The title compounds were screened for histamine antagonistic activity at the isolated ileum (H1R) and the isolated spontaneously beating right atrium (H2R) of the guinea pig. The results indicate that, depending on the nature of the H2R antagonist partial structure, the highest H1R antagonist potency resided in roxatidine-type compounds with spacers of six methylene groups in length (compound 21), and tiotidine-type compounds irrespective of the alkyl chain length (compounds 28, 32, 33), N-cyano-N'-[2-[[(2-guanidino-4-thiazolyl)methyl]thio]ethyl]-N″-[2-[N-[2-[N-(4-methoxybenzyl)-N-(pyridyl)-amino] ethyl]-N-methylamino]ethyl] guanidine (25, pKB values: 8.05 (H1R, ileum) and 7.73 (H2R, atrium) and the homologue with the mepyramine moiety connected by a six-membered chain to the tiotidine-like partial structure (compound 32, pKB values: 8.61 (H1R) and 6.61 (H2R) were among the most potent hybrid compounds. With respect to the development of a potential pharmacotherapeutic agent, structural optimization seems possible through selection of other H1R and H2R pharmacophoric moieties with mutually affinity-enhancing properties.
    Molecules 01/2013; 18(11):14186-202. · 2.43 Impact Factor
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    ABSTRACT: Bivalent histamine H(2) receptor (H(2)R) agonists were synthesized by connecting pharmacophoric 3-(2-amino-4-methylthiazol-5-yl)-, 3-(2-aminothiazol-5-yl)-, 3-(imidazol-4-yl)-, or 3-(1,2,4-triazol-5-yl)propylguanidine moieties by N(G)-acylation with alkanedioic acids of various chain lengths. The compounds were investigated for H(2)R agonism in GTPase and [(35)S]GTPγS binding assays at guinea pig (gp) and human (h) H(2)R-Gsα(S) fusion proteins including various H(2)R mutants, at the isolated gp right atrium, and in GTPase assays for activity on recombinant H(1), H(3), and H(4) receptors. The bivalent ligands are H(2)R partial or full agonists, up to 2 orders of magnitude more potent than monovalent acylguanidines and, with octanedioyl or decanedioyl spacers, up to 4000 times more potent than histamine at the gpH(2)R. In contrast to their imidazole analogues, the aminothiazoles are highly selective for H(2)R vs other HR subtypes. Compounds with (theoretically) sufficient spacer length (20 CH(2) groups) to simultaneously occupy two orthosteric binding sites in H(2)R dimers are nearly inactive, whereas the highest potency resides in compounds with considerably shorter spacers. Thus, there is no evidence for interaction with H(2)R dimers. The high agonistic potency may result from interaction with an accessory binding site at the same receptor protomer.
    Journal of Medicinal Chemistry 01/2012; 55(3):1147-60. · 5.61 Impact Factor
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    ABSTRACT: In literature, a synergism between histamine H(1) and H(4) receptor is discussed. Furthermore, it was shown, that the combined application of mepyramine, a H(1) antagonist and JNJ7777120, a H(4) receptor ligand leads to a synergistic effect in the acute murine asthma model. Thus, the aim of this study was to develop new hybrid ligands, containing one H(1) and one H(4) pharmacophor, connected by an appropriate spacer, in order to address both, H(1)R and H(4)R. Within this study, we synthesized nine hybrid compounds, which were pharmacologically characterized at hH(1)R and hH(4)R. The new compounds revealed (high) affinity to hH(1)R, but showed only low affinity to hH(4)R. Additionally, we performed molecular dynamic studies for some selected compounds at hH(1)R, in order to obtain information about the binding mode of these compounds on molecular level.
    Bioorganic & medicinal chemistry letters 09/2011; 21(21):6274-80. · 2.65 Impact Factor
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    ABSTRACT: Histamine H1-receptor agonists and antagonists exhibit affinity to the human histamine H4-receptor (hH4R). However, the pharmacological profiles between hH1R and hH4R exhibit similarities and differences. Since suprahistaprodifen and trifluoromethylphenylhistamine show significant affinity to hH4R, the aim of this study was to analyse a large number of new phenylhistamines, histaprodifens and phenoprodifens at hH4R to extend the pharmacological profile of these compound classes at hH4R. The hH4R-RGS19 fusion protein was co-expressed with Gαi2 and Gβ1γ2 in Sf9 insect cells, and [3H]histamine competition binding as well as GTPase assays were performed. Based on adequate crystal structures, homology models of hH4R were generated. Molecular modelling studies, including molecular dynamics and prediction of Gibbs energy of ligand binding, were performed in order to explain the pharmacological data at hH4R on molecular level. The exchange of the phenyl moiety of phenylhistamines into the diphenylpropyl moiety of histaprodifens acts, in contrast to hH1R, as partial agonism–inverse agonism switch at hH4R. Based on our studies, some phenylhistamine derivatives with significantly higher affinity at hH4R than at hH1R were identified. The molecular dynamic simulations revealed two different conformations for the highly conserved Trp6.48, suggested to be involved in receptor activation. Furthermore, the predicted Gibbs energy of ligand binding for six selected phenylhistamines was in very good agreement with the experimentally determined affinities. We identified phenylhistamine derivatives with higher affinity at hH4R than at hH1R. Besides, we have identified partial agonism–inverse agonism switch between phenylhistamines and histaprodifens at hH4R. These results are very important to understand selectivity between hH1R and hH4R and to design new potent H1R and/or H4R receptor ligands. KeywordsHistamine H1 receptor–Histamine H4 receptor–Gibbs energy–Phenylhistamines–Histaprodifens
    Archiv für Experimentelle Pathologie und Pharmakologie 09/2011; 384(3):287-299. · 2.15 Impact Factor
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    ABSTRACT: 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.
    Planta Medica 02/2011; 77(10):973-8. · 2.35 Impact Factor
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    ABSTRACT: A series of dibenzo[b,e]ox(thi)epin-11(6H)-one O-benzoyloximes has been synthesized and structurally elucidated by means of IR, (1)H-NMR, (13)C-NMR, MS, and elemental analysis. The newly developed compounds were screened at concentrations of 200-25 μg/mL for their antibacterial activity against Gram+ve organisms such as Methicillin-Resistant Staphylococcus Aureus (MRSA), Gram-ve organisms such as Escherichia coli (E. coli), and at the same concentration range for their antifungal activity against fungal strain Aspergillus niger (A. niger) by the cup plate method. Ofloxacin and ketoconazole (10 μg/mL) were used as reference standards for antibacterial and antifungal activity, respectively. The dibenzo[b,e]oxepines 6a-c and 6e-h showed low antimicrobial activity (MIC 125-200 μg/mL) compared to the reference substances, whereas a major improvement (MIC 50-75 μg/mL) was achieved with the synthesis of the corresponding bromomethyl derivative 6d. Moreover, replacement of oxygen by its bioisosteric sulfur led to isomeric dibenzo[b,e]thi-epine derivatives 6g,h which significantly exhibited higher antimicrobial activity (MIC 25-50 μg/mL) against all tested culture strains used in the present study, demonstrating that a change of chemical class from dibenzo[b,e]oxepine to dibenzo[b,e]thiepine significantly improves the antimicrobial activity. Further variation, such as the oxidation of the thiepine sulfur to the corresponding isomeric dibenzo[b,e]thiepine 5,5-dioxide derivative 9, comparatively failed to exhibit high activity (MIC 200 μg/mL) against S. aureus, E. coli or A. niger.
    Scientia Pharmaceutica 01/2011; 79(4):749-61.
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    ABSTRACT: Problem statement: Several studies on the synthesis of new nifedipine analogs have beencarried out, but the literature reveled that no study on the synthesis and calcium channel blocking activity of the substituted ester with an amide (5-phenylcarbamoyl) moiety has been reported. Approach: Six new derivatives of m-nifedipine have been successfully synthesized by substituting an ester moiety with an amide (5-phenylcarbamoyl) moiety, using a modified Hantzsch reactions and tested for their pharmacological activities. The nifedipine analogs 1-6 were characterized and confirmed using elemental analysis, Infrared spectroscopy (IR), Nuclear Magnetic Resonance (1H NMR) and Mass spectroscopy. The purity of the compounds was ascertained by melting point and TLC. The in vitro calcium channel blocking activities were evaluated using the high K+ concentration of Porcine Coronary Artery Smooth Muscles(PCASM) assay. Results: The compounds (1-2) failed to exhibit any blocking activity (IC50 = 10−7 to 10−5 M range), while the compounds 3-6 relaxed precontracted porcine coronary artery smooth muscles with pEC50 values ranging between 4.37±0.10 (compound 3) and 6.46±0.07 (compound 5), indicating that compounds 3-6 exhibit comparable potencies in blocking calcium channels to reference drug varapamil (6.97±0.15) and m-nifedipine (6.48±0.05). Conclusion: The results of this study showed that some of the developed new compounds possess maximal calcium channel blocking effects comparable to m-nifedipine. The developed compounds in the present study will predicatively show an increased metabolic stability and consequently longer duration of actions compared to m-nifedipine and could be, therefore, suitable candidates for further optimization to be evaluated as a new class of antihypertensive drugs.
    American Journal of Applied Sciences, Volume 8 , Issue 4, p.303-309 (2011). 01/2011; 8:303-309.
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    ABSTRACT: A series of 51 5-HT(2A) partial agonistic arylethylamines (primary or benzylamines) from different structural classes (indoles, methoxybenzenes, quinazolinediones) was investigated by fragment regression analysis (FRA), docking and 3D-QSAR approaches. The data, pEC(50) values and intrinsic activities (E(max)) on rat arteries, show high variability of pEC(50) from 4 to 10 and of E(max) from 15 to 70%. FRA indicates which substructures affect potency or intrinsic activity. The high contribution of halogens in para position of phenethylamines to pEC(50) points to a specific hydrophobic pocket. Other results suggest the significance of hydrogen bonds of the aryl moiety for activation and the contrary effect of benzyl groups on affinity (increasing) and intrinsic activity (decreasing). Results from fragment regression and data on all available mutants were considered to derive a common binding site at the rat 5-HT(2A) receptor. After generation and MD simulations of a receptor model based on the β(2)-adrenoceptor structure, typical derivatives were docked, leading to the suggestion of common interactions, e.g., with serines in TM3 and TM5 and with a cluster of aromatic amino acids in TM5 and TM6. The whole series was aligned by docking and minimization of the complexes. The pEC(50) values correlate well with Sybyl docking energies and hydrophobicity of the aryl moieties. With this alignment, CoMFA and CoMSIA approaches based on a training set of 36 and a test set of 15 compounds were performed. The correlation of pEC(50) with steric, electrostatic, hydrophobic and H-bond acceptor fields resulted in sufficient fit (q (2): 0.75-0.8, r (2): 0.92-0.95) and predictive power (r (pred) (2) : 0.85-0.88). The important interaction regions largely reflect the patterns provided by the putative binding site. In particular, the fit of the aryl moieties and benzyl substituents to two hydrophobic pockets is evident.
    Journal of Computer-Aided Molecular Design 11/2010; 25(1):51-66. · 3.17 Impact Factor
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    ABSTRACT: ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
    ChemInform 06/2010; 32(26).
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    ABSTRACT: ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
    ChemInform 06/2010; 31(25).
  • ChemInform 06/2010; 31(25).
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    ABSTRACT: A set of chiral imidazolylpropylguanidines and 2-aminothiazolylpropylguanidines bearing N(G)-3-phenyl- or N(G)-3-cyclohexylbutanoyl residues was synthesized and investigated for histamine H(2) receptor (H(2)R) agonism (guinea pig (gp) right atrium, GTPase assay on recombinant gp and human (h)H(2)R) and for hH(2)R selectivity compared to hH(1)R, hH(3)R and hH(4)R. In contrast to previous studies on arpromidine derivatives, the present investigation of acylguanidine-type compounds revealed only very low eudismic ratios (1.1-3.2), indicating the stereochemistry of the acyl moiety to play only a minor role in this series of H(2)R agonists.
    Bioorganic & medicinal chemistry letters 05/2010; 20(10):3173-6. · 2.65 Impact Factor
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    ABSTRACT: ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
    ChemInform 01/2010; 26(51).
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    ABSTRACT: ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
    ChemInform 01/2010; 31(34).
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    ABSTRACT: ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
    ChemInform 01/2010; 30(2).
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    ABSTRACT: 3-(1H-Imidazol-4-yl)propylguanidine (SK&F 91486, 4) was identified as a potent partial agonist at the human histamine H(3) receptor (hH(3)R) and human histamine H(4) receptor (hH(4)R). With the aim to increase selectivity for the hH(4)R, the guanidine group in 4 was acylated. N(1)-Acetyl-N(2)-[3-(1H-imidazol-4-yl)propyl]guanidine (UR-PI288, 13) was a potent full agonist at the hH(4)R (pEC(50) = 8.31; alpha = 1.00), possessing more than 1000- and 100-fold selectivity relative to the hH(1)R and hH(2)R, respectively, and possessing only low intrinsic activity (alpha = 0.27) at the hH(3)R.
    Journal of Medicinal Chemistry 04/2009; 52(8):2623-7. · 5.61 Impact Factor
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    ABSTRACT: The inside cover picture shows the human histamine H(2) receptor and the H(2) and H(3)/H(4) receptor-selective ligands identified. Bioisosteric replacement of the imidazole ring of the N(G)-acyl-imidazolylpropylguanidine with 2-aminothiazole yielded potent and selective H(2) receptor agonists. In contrast, modification of the acyl group gave a high-affinity H(3)/H(4)-selective tritiated radioligand. For more details, see the Full Papers by A. Buschauer et al. on p. 225 ff and p. 232 ff.
    ChemMedChem 03/2009; 4(2):134. · 2.84 Impact Factor

Publication Stats

558 Citations
215.07 Total Impact Points


  • 2002–2014
    • Universität Regensburg
      • Institute of Pharmacy
      Ratisbon, Bavaria, Germany
    • Mansoura University
      • Department of Medicinal Chemistry
      Ṭalkha, Muhafazat ad Daqahliyah, Egypt
  • 2011–2013
    • United Arab Emirates University
      • Department of Pharmacology and Therapeutics
      Al Ain, Abu Dhabi, United Arab Emirates
  • 1988–2011
    • Freie Universität Berlin
      • Institute of Pharmacy
      Berlin, Land Berlin, Germany
  • 2010
    • Goethe-Universität Frankfurt am Main
      • Institut für Pharmazeutische Chemie
      Frankfurt, Hesse, Germany
  • 1987–2006
    • Johannes Gutenberg-Universität Mainz
      • Department of Pharmacology
      Mainz, Rhineland-Palatinate, Germany
  • 2002–2005
    • Jagiellonian University
      • Department of Chemical Technology
      Kraków, Lesser Poland Voivodeship, Poland
  • 2004
    • Ajman University of Science and Technology
      Ash Shāriqah, Ash Shāriqah, United Arab Emirates
  • 2003
    • Peking University
      • School of Pharmaceutical Sciences
      Beijing, Beijing Shi, China
    • University of Kansas
      • Department of Pharmacology and Toxicology
      Lawrence, KS, United States
  • 2001
    • Alexandria University
      • Department of Pharmaceutical Chemistry
      Alexandria, Alexandria, Egypt
  • 1995–2001
    • University of Bonn
      • Institute of Pharmacology and Toxicology
      Bonn, North Rhine-Westphalia, Germany
    • Clinical Hospital
      Ciudad de Montevideo, Montevideo, Uruguay
  • 2000
    • Collegium Medicum of the Jagiellonian University
      Cracovia, Lesser Poland Voivodeship, Poland