title: Blood-brain transfer and antinociception of linear and cyclic N-methyl-guanidine and thiourea-enkephalins.
abstract: Enkephalins are active in regulation of nociception in the body and are key in development of new synthetic peptide analogs that target centrally located opioid receptors. In this study, we investigated the in vivo blood-brain barrier (BBB) penetration behavior and antinociceptive activity of two cyclic enkephalin analogs with a thiourea (CycS) or a N-methyl-guanidine bridge (CycNMe), and their linear counterparts (LinS and LinNMe) in mice, as well as their in vitro metabolic stability. (125)I-LinS had the highest blood-brain clearance (K1=3.46μL/gmin), followed by (125)I-LinNMe, (125)I-CycNMe, and (125)I-CycS (K1=1.64, 0.31, and 0.11μL/gmin, respectively). Also, these peptides had a high metabolic stability (t1/2>1h) in mouse serum and brain homogenate, and half-inhibition constant (Ki) values in the nanomolar range with predominantly μ-opioid receptor selectivity. The positively charged NMe-enkephalins showed a higher antinociceptive activity (LinNMe: 298% and CycNMe: 205%), expressed as molar-dose normalized area under the curve (AUC) relative to morphine, than the neutral S-enkephalins (CycS: 122% and LinS: 130%).
authors.affiliation: Drug Quality and Registration (DruQuaR) group, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, B-9000 Ghent, Belgium.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Verbeken
authors.affiliation: Drug Quality and Registration (DruQuaR) group, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, B-9000 Ghent, Belgium.
authors.forename: Evelien
authors.initials: E
authors.lastname: Wynendaele
authors.affiliation: Institut des Biomolécules Max Mousseron, UMR5247 CNRS, Universités Montpellier 1 and 2, Faculty of Pharmaceutical Sciences, 15 Avenue Charles Flahault, F-34093 Montpellier, France.
authors.forename: Elodie
authors.initials: E
authors.lastname: Mauchauffée
authors.affiliation: Drug Quality and Registration (DruQuaR) group, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, B-9000 Ghent, Belgium.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Bracke
authors.affiliation: Drug Quality and Registration (DruQuaR) group, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, B-9000 Ghent, Belgium.
authors.forename: Sofie
authors.initials: S
authors.lastname: Stalmans
authors.affiliation: Biological Research Center, Institute of Biochemistry, POB 521, H-6702 Szeged, Hungary.
authors.forename: Engin
authors.initials: E
authors.lastname: Bojnik
authors.affiliation: Biological Research Center, Institute of Biochemistry, POB 521, H-6702 Szeged, Hungary.
authors.forename: Sandor
authors.initials: S
authors.lastname: Benyhe
authors.affiliation: Departments of Veterinary Medical Imaging and Small Animal Orthopaedics, Medicine and Clinical Biology of Small Animals and Comparative Physiology and Biometrics, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, B-9820 Merelbeke, Belgium.
authors.forename: Kathelijne
authors.initials: K
authors.lastname: Peremans
authors.affiliation: Departments of Veterinary Medical Imaging and Small Animal Orthopaedics, Medicine and Clinical Biology of Small Animals and Comparative Physiology and Biometrics, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, B-9820 Merelbeke, Belgium.
authors.forename: Ingeborgh
authors.initials: I
authors.lastname: Polis
authors.affiliation: Departments of Veterinary Medical Imaging and Small Animal Orthopaedics, Medicine and Clinical Biology of Small Animals and Comparative Physiology and Biometrics, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, B-9820 Merelbeke, Belgium.
authors.forename: Christian
authors.initials: C
authors.lastname: Burvenich
authors.affiliation: Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, Copenhagen University, Blegdamsvej 3, DK-2200 Copenhagen, Denmark.
authors.forename: Albert
authors.initials: A
authors.lastname: Gjedde
authors.affiliation: Institut des Biomolécules Max Mousseron, UMR5247 CNRS, Universités Montpellier 1 and 2, Faculty of Pharmaceutical Sciences, 15 Avenue Charles Flahault, F-34093 Montpellier, France.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Hernandez
authors.affiliation: Drug Quality and Registration (DruQuaR) group, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, B-9000 Ghent, Belgium. Electronic address: Bart.DeSpiegeleer@UGent.be.
authors.forename: Bart
authors.initials: B
authors.lastname: De Spiegeleer
mesh_terms: D000700:Analgesics / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000818:Animals; D019540:Area Under Curve; D001812:Blood-Brain Barrier / Q000378:metabolism*; D004353:Drug Evaluation, Preclinical; D004745:Enkephalins / Q000008:administration & dosage / Q000493:pharmacokinetics*; D006207:Half-Life; D020128:Inhibitory Concentration 50; D007276:Injections, Intraventricular; D008297:Male; D008760:Methylguanidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D008813:Mice, Inbred ICR; D059225:Nociception / Q000187:drug effects; D059226:Nociceptive Pain / Q000188:drug therapy; D017208:Rats, Wistar; D013890:Thiourea / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*
chemical_list: D000700:Analgesics; D004745:Enkephalins; D008760:Methylguanidine; D013890:Thiourea
keywords: Antinociceptive activity; Blood–brain barrier (BBB) transport (influx/efflux); In vivo mouse models; Linear/cyclic enkephalin analogs