Shuttle-cargo fusion molecules of transport peptides and the hD2/3 receptor antagonist fallypride: a feasible approach to preserve ligand-receptor binding?
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.
McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University , Montreal H3A 2B4, Canada.
Carmen
C
Wängler
Shafinaz
S
Chowdhury
Georg
G
Höfner
Petia
P
Djurova
Enrico O
EO
Purisima
Peter
P
Bartenstein
Björn
B
Wängler
Gert
G
Fricker
Klaus T
KT
Wanner
Ralf
R
Schirrmacher
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000737:chemistry; D000595:Amino Acid Sequence; D001549:Benzamides / Q000737:chemistry* / Q000493:pharmacokinetics; D001692:Biological Transport; D001812:Blood-Brain Barrier; D002352:Carrier Proteins / Q000737:chemistry*; D018492:Dopamine Antagonists / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D011990:Receptors, Transferrin / Q000378:metabolism; D057900:Transcytosis
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001549:Benzamides; D002352:Carrier Proteins; D018492:Dopamine Antagonists; D008024:Ligands; D017448:Receptors, Dopamine D2; D011990:Receptors, Transferrin; C574003:fallypride