Shuttle-Cargo fusion molecules of transport peptides and the hD 2/3 receptor antagonist fallypride : a feasible approach to preserve ligand-receptor binding?

Download
  1. (PDF, 1 MB)
  2. Get@NRC: Shuttle-Cargo fusion molecules of transport peptides and the hD 2/3 receptor antagonist fallypride : a feasible approach to preserve ligand-receptor binding? (Opens in a new window)
DOIResolve DOI: http://doi.org/10.1021/jm5004123
AuthorSearch for: ; Search for: ; Search for: ; Search for: ; Search for: ; Search for: ; Search for: ; Search for: ; Search for: ; Search for:
TypeArticle
Journal titleJournal of Medicinal Chemistry
ISSN0022-2623
Volume57
Issue10
Pages43684381; # of pages: 14
Subject3 [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; article; binding affinity; binding site; blood brain barrier; conjugate; conjugation; derivatization; drug synthesis; environmental temperature; freeze drying; high performance liquid chromatography; human; 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; Humans; Ligands; Models, Molecular; Molecular Docking Simulation; Molecular Sequence Data; P-Glycoprotein; Receptors, Dopamine D2; Receptors, Transferrin; Transcytosis
AbstractTo 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.
Publication date
LanguageEnglish
AffiliationHuman Health Therapeutics; National Research Council Canada
Peer reviewedYes
NPARC number21272728
Export citationExport as RIS
Report a correctionReport a correction
Record identifier7a4b49e4-755d-432e-be8b-7f3b45b51d2d
Record created2014-12-03
Record modified2016-05-09
Bookmark and share
  • Share this page with Facebook (Opens in a new window)
  • Share this page with Twitter (Opens in a new window)
  • Share this page with Google+ (Opens in a new window)
  • Share this page with Delicious (Opens in a new window)