- A new series of photoactivatable and iodinatable linear vasopressin antagonists
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A series of new linear photoactivatable and iodinatable antagonists of the neuropeptidic hormone vasopressin was designed and synthesized by a combination of PyBOP-mediated Boc/solid-phase peptide synthesis and solution synthesis approaches. These were based on modifications of a previously reported potent and selective antagonist of the vasopressor response (V(1a) receptor) to [arginine]vasopressin, phenylacetyl-D-Tyr(Me)-Phe-Gln-Asn-Arg- Pro-Arg-Tyr-NH2. (Azidophenyl)alkyl substitutions, of the general structure N3-C6H4(CH2)(n)CO (n = 0, 1, 2, or 3), were employed in position 1. The seven new analogues are 4-N3-C6H4CO-D-Tyr(Me)-Phe-Gln-Asn-Arg-Pro-Arg- Tyr-NH2 (3), 3-N3-C6H4CO-D-Tyr(Me)-Phe-Gln-Asn-Arg-Pro-Arg-Tyr-NH2 (12), 4-N3-C6H4CH2CO-D-Tyr(Me)-Phe-Gln-Asn-Arg-Pro-Arg-Tyr-NH2 (13), 3-N3- C6H4CH2CO-D-Tyr(Me)-Phe-Gln-Asn-Arg-Pro-Arg-Tyr-NH2 (14), 4-N3- C6H4(CH2)2CO-D-Tyr(Me)-Phe-Gln-Asn-Arg-Pro-Arg-Tyr-NH2 (15) 3-N3- C6H4(CH2)2CO-D-Tyr(Me)-Phe-Gln-Asn-Arg-Pro-Arg-Tyr-NH2 (16), 4-N3- C6H4(CH2)3CO-D-Tyr(Me)-Phe-Gln-Asn-Arg-Pro-Arg-Tyr-NH2 (17). All analogues were tested for their affinity of the rat hepatic V(1a) receptor. Analogues 3 and 12 have a low affinity (K(i) ? 20 nM) and analogues 13-17 show a high affinity (K(i) between 0.04 and 0.3 nM). The affinity values appear to be mainly a function of the alkyl chain length and to a lesser extent of the meta or para position of the azido group on the aromatic ring. Analogues 13-17 were iodinated on the Tyr-9 residue, giving compounds 18-22. All these five iodinated derivatives exhibited K(i) values of 0.2-1 nM for rat liver membranes. Their affinities for oxytocin and renal V2 vasopressin receptors were much lower. Moreover, all analogues completely antagonized the vasopressin-stimulated inositol phosphates production in WRK1 cells and were devoided of any agonistic potency. Preliminary covalent binding studies showed improved covalent yields as compared to any previously reported results. They are very promising candidates as potential high-affinity, highly selective, photosensitive ligands for the V(1a) receptor. They could serve as useful pharmacological tools for studies on the vasopressin binding site.
- Carnazzi,Aumelas,Barberis,Guillon,Seyer
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- Microfluidic preparation of89 zr-radiolabelled proteins by flow photochemistry
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89 Zr-radiolabelled proteins functionalised with desferrioxamine B are a cornerstone of diagnostic positron emission tomography. In the clinical setting,89 Zr-labelled proteins are produced manually. Here, we explore the potential of
- Earley, Daniel F.,Guillou, Amaury,Holland, Jason P.,Poot, Alex J.,van der Born, Dion
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- Light-Activated Protein Conjugation and 89Zr-Radiolabelling with Water-Soluble Desferrioxamine Derivatives
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Protein-conjugates are vital tools in biomedical research, drug discovery and imaging science. For example, functionalised monoclonal antibodies (mAbs) coupled to the desferrioxamine B (DFO) chelate and radiolabelled with 89Zr4+ ions
- Earley, Daniel F.,Guillou, Amaury,Holland, Jason P.
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- Targeting glycolysis: A fragment based approach towards bifunctional inhibitors of hLDH-5
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hLDH-5 has emerged as a promising target for anti-glycolytic cancer chemotherapy. Here we report a first generation of bifunctional inhibitors, which show promising activity against hLDH-5.
- Moorhouse, Adam D.,Spiteri, Christian,Sharma, Pallavi,Zloh, Mire,Moses, John E.
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supporting information; experimental part
p. 230 - 232
(2011/03/22)
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- A graftable LDV peptidomimetic: Design, synthesis and application to a blood filtration membrane
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A graftable LDV (Leu-Asp-Val) peptidomimetic molecule (B-c) has been prepared from 3-(5-amino-2-hydroxy)phenyl-propionic acid, as α4β1 (VLA-4) integrin ligand. For that purpose, the mechanism of 3-(4-azidophenyl)propionic acid rearrangement has been revisited. Activation of Durapore DVPP-hydrophilic membrane, by surface wet chemistry using triazine trifluoride, followed by covalent coupling of B-c produced a modified filter (0.8% of derivatisation from XPS analysis) with improved capacity of leukocyte retention.
- Momtaz, Maryam,Rerat, Vincent,Gharbi, Sonia,Gerard, Estelle,Pourcelle, Vincent,Marchand-Brynaert, Jacqueline
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p. 1084 - 1090
(2008/09/18)
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- Analogues of Capsaicin with Agonist Activity as Novel Analgesic Agents; Structure-Activity Studies. 3. The Hydrophobic Side-Chain "C-Region"
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Structural variants of the hydrophobic side chain ("C region") of the capsaicin molecule have been incorporated into a series of vanillylamides and vanillylthioureas.These compounds have been tested in an in vitro assay for agonism (45Ca2+ infl
- Walpole, Christopher S.J.,Wrigglesworth, Roger,Bevan, Stuart,Campbell, Elizabeth A.,Dray, Andy,et al.
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p. 2381 - 2389
(2007/10/02)
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- UTILIZATION OF A NITRENIUM ION CYCLIZATION IN A SYNTHESIS OF A PHOTOACTIVE PROSTAGLANDIN, 17-(4-AZIDO-2-HYDROXYPHENYL)-18,19,20-TRINORPROSTAGLANDIN F2α
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A nitrenium ion cyclization provided access to a suitably substituted arylpropionic ester needed in the synthesis of a potential prostaglandin photoaffinity probe, 17-(4-azido-2-hydroxyphenyl)-18,19,20-trinorprostaglandin F2α using the Corey synthesis.
- Dolence, E. Kurt,Morita, Hiroyuki,Watt, David S.,Fitz, Tony
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