title: Variation of the net charge, lipophilicity, and side chain flexibility in Dmt(1)-DALDA: Effect on Opioid Activity and Biodistribution.
abstract: The influence of the side chain charges of the second and fourth amino acid residues in the peptidic μ opioid lead agonist Dmt-d-Arg-Phe-Lys-NH(2) ([Dmt(1)]-DALDA) was examined. Additionally, to increase the overall lipophilicity of [Dmt(1)]-DALDA and to investigate the Phe(3) side chain flexibility, the final amide bond was N-methylated and Phe(3) was replaced by a constrained aminobenzazepine analogue. The in vitro receptor binding and activity of the peptides, as well as their in vivo transport (brain in- and efflux and tissue biodistribution) and antinociceptive properties after peripheral administration (ip and sc) in mice were determined. The structural modifications result in significant shifts of receptor binding, activity, and transport properties. Strikingly, while [Dmt(1)]-DALDA and its N-methyl analogue, Dmt-d-Arg-Phe-NMeLys-NH(2), showed a long-lasting antinociceptive effect (>7 h), the peptides with d-Cit(2) generate potent antinociception more rapidly (maximal effect at 1h postinjection) but also lose their analgesic activity faster when compared to [Dmt(1)]-DALDA and [Dmt(1),NMeLys(4)]-DALDA.
authors.affiliation: Department of Organic Chemistry, Vrije Universiteit Brussel, Pleinlaan 2, B-1050 Brussels, Belgium.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Novoa
authors.forename: Sylvia
authors.initials: S
authors.lastname: Van Dorpe
authors.forename: Evelien
authors.initials: E
authors.lastname: Wynendaele
authors.forename: Mariana
authors.initials: M
authors.lastname: Spetea
authors.forename: Nathalie
authors.initials: N
authors.lastname: Bracke
authors.forename: Sofie
authors.initials: S
authors.lastname: Stalmans
authors.forename: Cecilia
authors.initials: C
authors.lastname: Betti
authors.forename: Nga N
authors.initials: NN
authors.lastname: Chung
authors.forename: Carole
authors.initials: C
authors.lastname: Lemieux
authors.forename: Johannes
authors.initials: J
authors.lastname: Zuegg
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Cooper
authors.forename: Dirk
authors.initials: D
authors.lastname: Tourwé
authors.forename: Bart
authors.initials: B
authors.lastname: De Spiegeleer
authors.forename: Peter W
authors.initials: PW
authors.lastname: Schiller
authors.forename: Steven
authors.initials: S
authors.lastname: Ballet
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D001812:Blood-Brain Barrier; D001921:Brain / Q000187:drug effects; D051379:Mice; D015394:Molecular Structure; D059225:Nociception / Q000187:drug effects*; D009842:Oligopeptides / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D018847:Opioid Peptides / Q000378:metabolism; D010147:Pain Measurement / Q000187:drug effects*; D011957:Receptors, Opioid / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014018:Tissue Distribution
chemical_list: C424424:2',6'-dimethyltyrosyl-arginyl-phenylalanyl-lysinamide; D000701:Analgesics, Opioid; D009842:Oligopeptides; D018847:Opioid Peptides; D011957:Receptors, Opioid