Download | - View accepted manuscript: Shuttle-Cargo fusion molecules of transport peptides and the hD 2/3 receptor antagonist fallypride : a feasible approach to preserve ligand-receptor binding? (PDF, 1.8 MiB)
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DOI | Resolve DOI: https://doi.org/10.1021/jm5004123 |
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Author | Search for: Wängler, Carmen; Search for: Chowdhury, Shafinaz; Search for: Höfner, Georg; Search for: Djurova, Petia; Search for: Purisima, Enricho O.1; Search for: Bartenstein, Peter; Search for: Wängler, Björn; Search for: Fricker, Gert; Search for: Wanner, Klaus T.; Search for: Schirrmacher, Ralf |
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Affiliation | - National Research Council of Canada. Human Health Therapeutics
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Format | Text, Article |
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Subject | 3 [3 [(1 allylpyrrolidin 2 yl)methylcarbamoyl]4,5 dimethoxy phenyl] propyl thiol; butaclamol; carrier protein; chlorpromazine; cyclosporin A; dopamine 2 receptor; dopamine 2 receptor blocking agent; dopamine 3 receptor; dopamine 3 receptor blocking agent; drug carrier; fallypride; fluorine 18; gallium 68; haloperidol; ligand; maleimide; multidrug resistance protein; raclopride; transferrin receptor; unclassified drug; amino acid sequence; binding affinity; binding site; blood brain barrier; conjugate; conjugation; derivatization; drug synthesis; environmental temperature; freeze drying; high performance liquid chromatography; in vitro study; isotope labeling; ligand binding; membrane permeability; molecular docking; molecular model; molecule; nuclear localization signal; peptide synthesis; pH; positron emission tomography; reaction time; receptor binding; stereospecificity; transcytosis; Amino Acid Sequence; Benzamides; Biological Transport; Blood-Brain Barrier; Carrier Proteins; Dopamine Antagonists; Ligands; Models, Molecular; Molecular Docking Simulation; Molecular Sequence Data; P-Glycoprotein; Receptors, Dopamine D2; Receptors, Transferrin; Transcytosis |
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Abstract | To determine if the conjugation of a small receptor ligand to a peptidic carrier to potentially facilitate transport across the blood-brain barrier (BBB) by "molecular Trojan horse" transcytosis is feasible, we synthesized several transport peptide-fallypride fusion molecules as model systems and determined their binding affinities to the hD2 receptor. Although they were affected by conjugation, the binding affinities were found to be still in the nanomolar range (between 1.5 and 64.2 nM). In addition, homology modeling of the receptor and docking studies for the most potent compounds were performed, elucidating the binding modes of the fusion molecules and the structure elements contributing to the observed high receptor binding. Furthermore, no interaction between the hybrid compounds and P-gp, the main excretory transporter of the BBB, was found. From these results, it can be inferred that the approach to deliver small neuroreceptor ligands across the BBB by transport peptide carriers is feasible. |
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Publication date | 2014-04-30 |
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In | |
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Language | English |
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Peer reviewed | Yes |
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NPARC number | 21272728 |
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Export citation | Export as RIS |
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Report a correction | Report a correction (opens in a new tab) |
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Record identifier | 7a4b49e4-755d-432e-be8b-7f3b45b51d2d |
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Record created | 2014-12-03 |
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Record modified | 2020-06-04 |
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