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PubMed2000

Different neurorescue profiles of selegiline and p-fluoro-selegiline in gerbils.

The neuroprotective/neuronal rescue effects of selegiline are not exactly understood, and show great variability in clinical trials. In this study, the dose-dependence of neuronal rescue potency of selegiline and its analogue para-fluoro-selegiline (PFS) was investigated in gerbils. The compounds were tested in a transient global cerebral ischemia model. Selegiline expressed a bell-shaped, dose-response curve with high intrinsic activity (with greatest effect at 0.001 mg/kg), as opposed to PFS which shows a saturation profile. These findings indicate possible therapeutic differences between PFS and selegiline in the treatment of neurodegenerative disorders. Inhibition of progression of the disease (neuroprotective effect) and improvements of symptoms (MAO-B inhibition) may occur at the same dose level using PFS, while these doses are separated in case of selegiline.

Animals↗
PubMed2003

Diffuse reflection infrared Fourier transform (DRIFT) spectra and high-temperature DRIFT spectra of beta-Ni(IO3)2.4H2O, Ni(IO3)2.2H2O, Mg(OH)2, and Zn(OH)F: novel embedding materials.

Diffuse reflection infrared Fourier transform (DRIFT) spectra of the hydroxides Mg(OH)2 and Zn(OH)F and the iodate hydrates beta-Ni(IO3)2.4H2O and Ni(IO3)2.2H2O have been recorded at ambient and high temperature. Spectra without shifts of the band maxima compared to those of conventional infrared transmission spectra and without inversion of the bands were obtained by dilution of the compounds to about 2-10% with an appropriate embedding material. alpha-Al2O3, TiO2, ZrO2, PbF2, MgO, BaO, ZnO, Na2SiO3, SiO2 (aerosil), and powdered copper, aluminum, and magnesium were tested as diluents for hydrates and hydroxides, especially at elevated temperatures, as alternatives for the commonly used KBr. Thus, alpha-Al2O3, PbF2, and powdered copper were established as the most favorable diluents. Using these novel embedding materials, high-temperature DRIFT spectra are obtainable at temperatures not accessible with KBr discs. Dehydration and decomposition of the iodate hydrates under study were shown by change or disappearance of the respective water bands.

Fluorine Compounds↗
PubMed2002

PAH degradation by UV/H2O2 in perfluorinated surfactant solutions.

Polycyclic aromatic hydrocarbons (PAHs) solubilized in perfluorinated surfactant (PFS) solutions were degraded by direct photolysis and UV/H2O2 process. The subsequent recovery and reuse of these surfactant solutions were also demonstrated. Phenanthrene and pyrene were selected as representative PAHs and an anionic PFS: ammonium perfluorooctanoate (APFO) was used. In our experiments, micellar APFO solutions retarded the phenanthrene photolysis and enhanced the pyrene photolysis. The results indicate that the photochemical reactivity of compound in micelles is strongly dependent on specific properties of the solubilizate, possibly due to the different excited state behaviors of compound. UV/H2O2 process exhibits a greatly enhanced rate of PAH photolysis in both water and APFO compared to direct photolysis. indicating that hydroxyl radicals may be generated or penetrated at the sites of PAHs solubilized in the micelles. Additionally. a smaller rate enhancement by UV/H2O2 in micelles than in water suggests that micelles provide some degree of protection from hydroxyl radical attack. The possibility of recovery and reuse of PFS has been demonstrated by measuring the solubilizing capacity of APFO after direct photolysis and UV/H2O2 process. Overall, this study demonstrates UV/H2O2 process can be an effective treatment method for not only PAH degradation but also surfactant recovery and reuse.

Fluorine Compounds↗
PubMed2006

Organofluorine inhibitors of amyloid fibrillogenesis.

The design and application of an effective, new class of organofluorine inhibitors of amyloid fibrillogenesis are described. Based on experimental evidence a core structure containing indol-3-yl, trifluoromethyl, hydroxyl, and carboxylic acid ester functions has been designed. Several substituted derivatives of this core structure have been synthesized, using various indole derivatives. While all inhibitor candidates have shown considerable effect (20-70% inhibition) in structure-activity relationship studies (inhibitor/Abeta = 10 ratio), several compounds have demonstrated excellent activity (93-96% inhibition). Using concentration dependence studies, the activity of the most active molecules have been quantified. These inhibitors practically completely block the fibril formation of Abeta(1)(-)(40), as shown by maximum inhibition values (IC(max) = 98-100%). The median inhibitor concentration values (IC(50) = 0.23-0.53 mol(inhibitor)/mol(A)(beta)) demonstrate favorable stoichiometry for the inhibition. The respective elimination of the functional groups from the core structure has resulted in a partial or complete loss of activity, indicating the significant role of each group. Experiments with these derivatives suggest the particular importance of the acidic hydroxyl group during peptide-inhibitor interaction.

Amyloid beta-Peptides↗
PubMed2003

Synthesis, characterization and biological evaluation of 7 alpha-perfluoroalkylestradiol derivatives.

Linkage of a long CH(2 )side chain ('spacer') onto C-7 alpha of estradiol-17 beta (E(2)) does not abrogate the binding affinity of this hormone for its receptor. Our purpose was to assess whether the linkage of a CF(2 )side chain, which is more bulky and rigid, could also be accommodated by the estrogen receptor (ER). We describe here the synthesis of 7 alpha-perfluorohexylestradiol 7 by perfluoroalkylation of a key silylenolether 2 with FITS-6 (perfluorohexyl-phenyliodoniurn trifluoromethanesulfonate). 7 alpha-Trifluoromethylestradiol 10a was prepared as a fluorinated control compound by UV-light induced trifluoromethylation of 2 with Umemoto reagent (S-trifluoromethyldibenzo[b,d]thiophenium trifluoromethanesulfonate). Endocrine properties of these two E(2 )derivatives were tested on the MCF-7 breast cancer cell line. Our data reveal that rigidity of the side chain of 7 affected the association of its hormone moiety with the ER to the same extent as a long alkyl side chain. Rigidity also failed to abrogate estrogenicity, as demonstrated by the ability of 7 to enhance ERE-dependent transcription and cell growth. Compound retained the capacity of inducing down regulation of the receptor. Interestingly, no evidence of antiestrogenicity was recorded since this compound behaved like a weak estrogen, exerting a mitogenic effect at high concentration. Of note, control 10a displayed a higher binding affinity than 7 for ER and consequently acted like the latter, albeit with a higher efficiency. Selection of appropriate residues to be linked at the end of a long 7 alpha alkyl side chain is known to be essential for generating strong antiestrogenicity. One may hope that such a property may also hold for perfluorinated chains to produce antiestrogens with strong metabolic stability.

Alkylation↗
PubMed2005

Fluorotelomer carboxylic acids and PFOS in rainwater from an urban center in Canada.

A method based on LC/MS/MS analysis of fluorotelomer carboxylic acids (FTCAs: CnF2n+1CH2COOH, n = 6, 8, and 10) and fluorotelomer unsaturated carboxylic acids (FTUCAs: CnF2nCHCOOH, n = 6, 8, and 10) in rainwater using negative ionization electrospray multiple reaction monitoring conditions is described. These compounds are thought to be oxidative products of atmospherically transported fluorotelomer alcohols (FTOHs: CnF2n+1CH2CH2CH2OH). Preconcentration from rainwater samples collected in Winnipeg, Manitoba, Canada, was achieved using solid-phase extraction on C18 sorbent. Low parts per trillion levels of the C10- and C12-FTCAs and FTUCAs were detected, suggesting that one possible pathway of removing FTOHs from the atmosphere is through oxidation and wet deposition. Perfluorocarboxylic acids (PFCAs) and perfluorooctane sulfonate (PFOS) were simultaneously analyzed in the rainwater samples using established LC/MS/MS methods. PFOS was deposited in rainwater with a concentration of 0.59 ng/L while PFCAs were not detected above their respective method detection limits.

Air Pollutants↗
PubMed2004

A novel imaging probe for in vivo detection of neuritic and diffuse amyloid plaques in the brain.

Extensive deposition of neuritic and diffuse amyloid plaques in the brain is a critical event for the pathogenesis of Alzheimer's disease (AD) and considered to start before the appearance of clinical symptoms. In vivo detection of these brain beta-amyloid (Abeta) deposits using positron emission tomography (PET), therefore, would be a useful marker for presymptomatic detection of AD. To develop a new agent for PET probe of imaging neuritic and diffuse amyloid deposits, novel fluorescent compounds, including styryl-fluorobenzoxazole derivatives, were examined. These compounds showed a high binding affinity for both synthetic Abeta1-40 and Abeta1-42 aggregates. Some of these compounds also displayed distinct staining of neuritic and diffuse amyloid plaques in AD brain sections. A biodistribution study of styryl-fluorobenzoxazole derivatives in normal mice exhibited excellent brain uptakes (4.5-5.5% injected dose/g at 2 min postinjection). Furthermore, iv administration of BF-145, a styryl-fluorobenzoxazole derivative, demonstrated specific in vivo labeling of compact and diffuse amyloid deposits in an APP23 transgenic mouse brain, in contrast to no accumulation in a wild-type mouse brain. These findings suggest that BF-145 is a potential candidate as a probe for imaging early brain pathology in AD patients.

Aged↗
PubMed1994

(Trifluoromethyl)lumazine derivatives as 19F NMR probes for lumazine protein.

Lumazine protein acts as an electronic excited state transducer in bioluminescence of Photobacterium species. The protein binds 6,7-dimethyl-8-(D-ribityl)lumazine (1) which serves as the fluorophore. This compound also serves as a biosynthetic precursor of riboflavin and is the substrate of the enzyme riboflavin synthase. This enzyme and lumazine protein show considerable sequence homology. The interaction of lumazine apoprotein with several trifluoromethyl analogs of 6,7-dimethyl-8-ribityllumazine was investigated by 19F NMR spectroscopy. Upon binding to the protein, the 19F NMR resonances of the ligand shift to lower field with broadened line widths to around 30 Hz. By comparison, all ligands studied show more complex NMR spectra when bound to riboflavin synthase. Only one position 7 epimer (designated epimer A) of 6,7-bis(trifluoromethyl)-7-hydroxy-8-(D-ribityl)lumazine binds to lumazine apoprotein and riboflavin synthase. The apoprotein can also bind lumazine derivatives with a quarternary C-7. It is suggested that the binding site of lumazine protein corresponds to the donor binding site of riboflavin synthase.

Fluorine Compounds↗
PubMed2001

Efficacy of hexafluorine for emergent decontamination of hydrofluoric acid eye and skin splashes.

Hexafluorine is an amphoteric, hypertonic, polyvalent compound for decontaminating hydrofluoric acid (HF) eye and skin splashes. In a German metallurgy facility during the period of 1994-1998, all eye or skin splashes with 40% HF alone or with a 6% HF/15% HNO3 mixture were initially decontaminated with Hexafluorine within 2 min following the splash at the accident site by the victims themselves or co-workers who witnessed the accident. Eleven workers using 40% HF or a 6% HF/15% HNO3 mixture sustained eye (2 cases) or skin (10 cases) splashes (1 combined) during 1994-1998. Hexafluorine was used within 2 min, and a second Hexafluorine decontamination was done on arrival at the plant infirmary. No further medical or surgical treatment was needed, no workers developed chemical burns, and none lost work time. These II cases demonstrate the efficacy of Hexafluorine in decontaminating HF or combined HF/HNO3 splashes.

Accidents, Occupational↗
PubMed2003

Vitamin C metabolomic mapping in experimental diabetes with 6-deoxy-6-fluoro-ascorbic acid and high resolution 19F-nuclear magnetic resonance spectroscopy.

Metabolomic mapping is an emerging discipline geared at providing information on a large number of metabolites as a complement to genomics and proteomics. Here we have probed ascorbic acid homeostasis and degradation in diabetes using 6-deoxy-6-fluoro ascorbic acid (F-ASA) and 750 MHz (19)F-nuclear magnetic resonance (NMR) spectroscopy with proton decoupling In vitro, Cu(2+)-mediated degradation of F-ASA revealed the formation of 4 major stable degradation products at 24 hours. However, when normal or diabetics rats were injected with F-ASA intraperitoneally (IP) for 4 days, up to 20 fluorine-labeled compounds were observed in the urine. Their composition resembled, in part, metal catalyzed degradation of F-ASA and was not explained by spontaneous degradation in the urine. Diabetes led to a dramatic increase in urinary F-ASA loss and a relative decrease in most other urinary F-compounds. Diabetes tilted F-ASA homeostasis toward oxidation in liver (P <.01), kidney (P <.01), spleen (P <.01), and plasma (P <.01), but tended to decrease oxidation in brain, adrenal glands, and heart. Surprisingly, however, besides the major oxidation product fluoro-dehydroascorbic acid (F-DHA), no F-ASA advanced catabolites were detected in tissues at 5 micromol/L sensitivity. These findings not only confirm the key role of the kidney in diabetes-mediated loss of ascorbic acid, but demonstrate that only selected tissues are prone to increased oxidation in diabetes. While the structure of most degradation products needs to be established, the method illustrates the power of high resolution (19)F-NMR spectroscopy for the mapping of complex metabolomic pathways in disease states.

2,3-Diketogulonic Acid↗
PubMed2004

Selection of 2'-fluoro-modified RNA aptamers for alleviation of cocaine and MK-801 inhibition of the nicotinic acetylcholine receptor.

The nicotinic acetylcholine receptor (nAChR) belongs to a group of five structurally related proteins that regulate signal transmission between approximately 10(12) cells of the mammalian nervous system. Many therapeutic agents and abused drugs inhibit the nAChR, including the anti-convulsant MK-801 and the abused drug cocaine. Many attempts have been made to find compounds that prevent inhibition by cocaine. Use of transient kinetic techniques to investigate the inhibition of the receptor by MK-801 and cocaine led to an inhibition mechanism not previously proposed. The mechanism led to the development of combinatorially synthesized RNA ligands that alleviate inhibition of the receptor. However, these ligands are relatively unstable. Here we determined whether much more stable 2'-fluoro-modified RNA ligands can be prepared and used to study the alleviation of receptor inhibition. Two classes of 2'-fluoro-modified RNA ligands were obtained: One class binds with higher affinity to the cocaine-binding site on the closed-channel form and, as predicted by the mechanism, inhibits the receptor. The second class binds with equal or higher affinity to the cocaine-binding site on the open-channel form and, as predicted by the mechanism, does not inhibit the receptor, and does alleviate cocaine and MK-801 inhibition of the nAChR. The stability of these 2'-fluoro-RNAs expands the utility of these ligands.

Animals↗
PubMed2005

Perfluorinated compounds in the plasma of loggerhead and Kemp's ridley sea turtles from the southeastern coast of the United States.

Perfluorinated compounds (PFCs) have been measured in blood of humans and wildlife and are considered globally distributed contaminants. We examined 12 PFCs in the plasma of 73 loggerhead sea turtles (Caretta caretta) and 6 Kemp's ridley sea turtles (Lepidochelys kempii) captured from inshore waters of Core Sound, North Carolina (NC), and offshore waters of South Carolina, Georgia, and Florida (SC-FL). Perfluorooctanesulfonate (PFOS) and perfluorooctanoic acid (PFOA) were the dominant compounds, with respective mean concentrations of 11.0 ng/mL and 3.20 ng/mL for loggerhead turtles and 39.4 ng/mL and 3.57 ng/mL for Kemp's ridley turtles. Mean PFOS concentrations were 2- to 12-fold higher than typical mean sigmaPCB concentrations (approximately 5 ng/g wet mass) measured previously in sea turtle blood. More than 79% of the samples had detectable levels of perfluorocarboxylates (PFCAs) with 8-12 carbons, whereas only 17% or less of samples had detectable levels of PFCAs with 6 or 7 carbons. No samples had detectable levels of PFCAs with 4 or 5 carbons. In loggerhead turtles, sigmaPFC concentrations were not influenced by sex (p > 0.05), but were higher in turtles captured from inshore waters of NC than in turtles from offshore waters of SC-FL (p = 0.009). A backward stepwise multiple regression model showed that sigmaPFC concentrations were (1) significantly higher in Kemp's ridley turtles than loggerhead turtles (p < 0.0001), (2) higher in larger turtles (p = 0.018; carapace length used as a proxy for age), and (3) higher in turtles captured toward the north (p = 0.006). These findings suggest that bioaccumulation of PFCs in sea turtles is influenced by species, age, and habitat.

Animals↗
PubMed2003

Spectra and structure of silicon containing compounds. XXXIX. Raman and infrared spectra, conformational stability, vibrational assignment and ab initio calculations of n-propyltrifluorosilane.

The infrared (3100-40 cm(-1)) spectra of gaseous and solid and Raman (3200-20 cm(-1)) spectra of liquid with qualitative depolarization values and solid n-propyltrifluorosilane, CH(3)CH(2)CH(2)SiF(3), have been recorded. Additionally the infrared spectra of the sample in nitrogen and argon matrices have been recorded. Both the anti and gauche conformers have been identified in the fluid phases but only the anti conformer remains in the solid. Variable temperature (-105 to -150 degrees C) studies of the infrared spectra of the sample dissolved in liquid krypton have been recorded and the enthalpy difference has been determined to be 135+/-14 cm(-1) (1.62+/-0.17 kJ mol(-1)) with the anti conformer the more stable form. At ambient temperature it is estimated that there is 51+/-2% of the gauche conformer present. Also the enthalpy difference in the liquid was obtained from variable temperature studies of the Raman spectra and from three conformer pairs an average value of 179+/-18 cm(-1) (2.14+/-0.22 kJ mol(-1)) was obtained again with the anti form the more stable conformer. Relatively complete vibrational assignments are proposed for both conformers based on the relative infrared and Raman spectral intensities, infrared band contours, depolarization ratios which are supported by normal coordinate calculations. The geometrical parameters, harmonic force constants, vibrational frequencies, infrared intensities, Raman activities, depolarization ratios, and energy differences have been obtained for the anti and gauche conformers from ab initio MP2/6-31G(d) calculations. Structural parameters and energy differences have also been obtained utilizing the larger 6-311+G(d, p) and 6-311+G(2d, 2p) basis sets. By utilizing the previously reported microwave rotational constants for five isotopomers of CH(3)SiF(3) along with ab initio predicted structural values, r(0) parameters have been obtained for methyltrifluorosilane. Similarly, from the ab initio predicted parameters "adjusted r(0)" parameters have been estimated for both conformers of n-propyltrifluorosilane. The results are discussed and compared with those obtained for some similar molecules.

Cold Temperature↗
PubMed2006

Fluoroolefins as peptide mimetics: a computational study of structure, charge distribution, hydration, and hydrogen bonding.

The design of peptide mimetic compounds is greatly facilitated by the identification of functionalities that can act as peptide replacements. The fluoroalkene moiety has recently been employed for that purpose. The purpose of this work is to characterize prototypical fluoroalkenes (fluoroethylene and 2-fluoro-2-butene) with respect to key properties of peptides (amides) including structure, charge distribution, hydration, and hydrogen bonding. The results are compared to those obtained for model peptides (formamide, N-methylacetamide). Calculations have been carried out at the MP2 and B3LYP levels of theory with the 6-311++G(2d,p) and 6-311++G(2d,2p) basis sets. The results suggest that the fluoroalkene is similar in steric requirements to a peptide bond but that there is less charge separation. Calculations of the hydration free energies with the PCM bulk continuum solvent model indicate that the fluoroalkene has much smaller hydration free energies than an amide but that the difference in solvation free energy for cis and trans isomers is comparable. In studies of complexes with water molecules, the fluoroalkene is found to engage in interactions that are analogous to backbone hydrogen-bonding interactions that govern many properties of natural peptides and proteins but with smaller interaction energies. In addition, key structural differences are noted when the fluoroalkene is playing the role of hydrogen-bond acceptor which may have implications in binding, aggregation, and conformational preferences in fluoroalkene peptidomimetics. The issue of cooperativity in hydrogen-bonding interactions in complexes with multiple waters has also been investigated. The fluoroalkene is found to exhibit cooperative effects that mirror those of the peptide but are smaller in magnitude. Thus, pairwise addivitity of interactions appears to more adequately describe the fluoroalkenes than the peptides they are intended to mimic.

Alkenes↗
PubMed2002

Topical treatments for hydrofluoric acid burns: a blind controlled experimental study.

BACKGROUND: Calcium gluconate gel, applied after initial rinsing with water, has a documented effect as first aid treatment for hydrofluoric acid burns. Hexafluorine is a novel liquid compound developed especially for emergency decontamination of hydrofluoric acid eye and skin exposures. However, scientific documentation of the effect of Hexafluorine is insufficient. This study was undertaken to compare Hexafluorine with water rinsing plus topical calcium and with water rinsing alone. METHODS: Thirty-five Sprague-Dawley rats were anesthetized and their backs shaved. Four filter papers 10 mm in diameter were soaked in 50% hydrofluoric acid and applied on the shaved area of each rat for 3 minutes. Thirty seconds later, the acid-exposed skin areas were rinsed with 500 mL Hexafluorine for 3 minutes (group H, n = 10), 500 mL water for 3 minutes (group W, n = 10) or 500 mL water for 3 minutes followed by a single application of 2.5% calcium gluconate gel (group Ca, n = 10), or received no treatment (controls, n = 5). The animals were closely observed for 5 days. Daily at 4 P.M. each of the four burns on every rat was rated on a modified Draize scale graded from 0 to 5 (0 = no visible injury, 1 = diffuse erythema, 2 = distinct erythema, 3 = distinct erythema plus wounds or discolored spots, 4 = distinct erythema plus wounds or discolored areas covering >50% of the burn, 5 = a necrotic wound covering the whole burn). The mean of the four scores was then calculated for each animal and day. The rating procedure was performed by one laboratory assistant who was unaware of the treatment given. Kruskal-Wallis analysis was used to evaluate possible differences between treatment groups on each of the 5 days. If the p-value obtained was <0.05, correction for multiple comparisons was made. RESULTS: The mean severity score in group H was significantly higher than that in group Ca on days 2 and 3. Moreover, Hexafluorine showed a consistent trend towards a worse outcome, both in comparison to water plus topical calcium and to water rinsing alone. CONCLUSION: Based on these observations it is concluded that water rinsing followed by topical calcium should remain the standard first aid treatment for skin exposure to hydrofluoric acid.

Animals↗
PubMed1999

Parallel synthesis with fluorous reagents and reactants.

Fluorous reagents and reactants provide emerging new options in parallel synthesis because they are easily prepared, reacted, and then separated from the desired reaction products. Some background information on fluorous reaction and separation techniques is provided, and the utility of fluorous reagents and reactants is illustrated with a number of case studies that feature both liquid-liquid and solid-solid separations.

Alkylation↗
PubMedDate not supplied

A molecular dynamics study of the three-dimensional model of human synovial fluid phospholipase A2--transition state mimic complexes.

Different modes of binding of transition state mimics: amide, phosphonate and difluoro ketone, to human synovial fluid phospholipase A2 (HSF PLA2) are studies by molecular dynamics simulations computed in solvent. The results are analysed in the light of primary binding sites. Hydrogen bonding interaction plays an important role for amino acids such as Gly32, Val30, and Glu55, apart from the well known active site residues viz Asp48, Gly25, Gly29, Gly31, His27, His47, Lys62, Phe23, Asn114 and Tyr112. In addition, the hydrogen bonding interaction between Sn-1 tetrahedral phosphonate group of amide and difluoro ketone inhibitors and crystallographic water molecules (H2O 523, H2O 524 and H2O 401) seems to have a significant role. Many of the active site charged residues display considerable movement upon ligand binding. The structural effects of ligand binding were analyzed from RMS deviations of C alpha in the resulting energy-minimized average structures of the receptor-ligand complexes. The values of the RMS deviations differ among the HSF PLA2s, in a pattern that is not the same for the three complexes. This suggests that ligands with different pharmacological efficacies induce different types of conformational changes of the receptor. Our active-orientation model is, at least qualitatively, consistent with experimental data and should be useful for the rational design of more potent inhibitors.

Amides↗
PubMed1998

Bradykinin antagonists with dehydrophenylalanine analogues at position 5.

Continuing the studies on structural requirements of bradykinin antagonists, it has been found that analogues with dehydrophenylalanine (deltaPhe) or its ring-substituted analogues (deltaPhe(X)) at position 5 act as antagonists on guinea pig pulmonary artery, and on guinea pig ileum. Because both organs are considered to be bradykinin B2 receptor tissues, the analogues with deltaPhe or deltaPhe(X) at position 5, but without any replacement at position 7, seem to represent a new structural type of B2 receptor antagonist. All the analogues investigated act as partial antagonists; they inhibit the bradykinin-induced contraction at low concentrations and act as agonists at higher concentrations. Ring substitutions by methyl groups or iodine reduce both the agonistic and antagonistic activity. Only substitution by fluorine gives a high potency. Incorporation of deltaPhe into different representative antagonists with key modifications at position 7 does not enhance the antagonist activity of the basic structures, with one exception. Only the combination of deltaPhe at position 5 with DPhe at position 7 increases the antagonistic potency on guinea pig ileum by about one order of magnitude. Radioligand binding studies indicate the importance of position 5 for the discrimination of B2 receptor subtypes. The binding affinity to the low-affinity binding site (KL) was not significantly changed by replacement of Phe by deltaPhe. In contrast, ring-methylation of deltaPhe results in clearly reduced binding to KL. The affinity to the high-affinity binding site (KH) was almost unchanged by the replacement of Phe in position 5 by deltaPhe, whereas the analogue with 2-methyl-dehydrophenylalanine completely failed to detect the KH-site. The peptides were synthesized on the Wang-resin according to the Fmoc/Bu(t) strategy using Mtr protection for the side chain of Arg. The dehydrophenylalanine analogues were prepared by a strategy involving PyBop couplings of the dipeptide unit Fmoc-Gly-deltaPhe(X)-OH to resin-bound fragments.

Animals↗