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Design, Synthesis and Characterization of Galanin Receptor Selective Ligands

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Design, Synthesis and Characterization of Galanin Receptor Selective Ligands !" #$"% "!&$$ ' () * ( +",-& . #/0!$ !$ 1 &2 . &2 "3 ( &. 4 . ( ( ( . &5 ( &6 ( ( 4 ( ( 4 & 0 & ( & 2 & " # (3 7#""8&9 (. : 4 4 & # 4 4 "& ( . : & ! # : & ; &7!/<8 4 & 9 ( ( & !" #$"% =00 && 0 > ? == = = "!/@@$ 9-/%@/"%,;/%#"$ 9-/%@/"%,;/%##% # $% # ("$,/" Design, Synthesis and Characterization of Galanin Receptor Selective Ligands Kristin Webling Abstract Galanin is a 29/30 amino acid long bioactive peptide discovered over 30 years ago when C-terminally amidated peptides were isolated from porcine intestines. The name galanin originates from a combination of the first and last amino acids - G from glycine and the rest from alanine. The first 15 amino acids are highly conserved throughout species, which indicates that the N-terminus is important for receptor recognition and binding. Galanin exerts its effects by binding to three different G protein-coupled receptors, which all differ according to regional distribution, the affinity for shortened galanin fragments, as well as the intracellular G-protein signaling cascade used. When first discovered, galanin was found to cause muscle contraction as well as hyperglycemia. Over the years, galanin has been reported to be involved in a wide variety of biological functions, for example food intake and neurogenesis, and pathological functions, for example epilepsy and de- pression. Determining the specific involvement of the three different galanin recep- tors in biological and pathological processes is limited by the small amount of galanin receptor selective/specific ligands available as research tools. Furthermore, the fast degradation of peptides limits the administration routes in animal studies. This thesis aims at developing new galanin receptor-selective ligands to help delineate the involvement of the three different galanin receptors. Paper 1 presents the shortest galanin fragment with a galanin receptor 2 specific binding preference where only a single amino acid substitution was made, Ala5Ser in galanin (2-11). In addition, G-protein coupled receptor signaling were evaluated through both a classical second messenger assay and a real-time label-free technique in cells overexpressing the receptor as well as low receptor expression. Paper 2 demonstrates that the neuroprotective effects of galanin in a kainic acid-induced excitotoxic animal model were mediated through galanin receptor 1. Furthermore, a new robust protocol for evaluating G- protein signaling using a label-free real time impedance technique was pre- sented and compared to two different classical second-messenger assays. Paper 3 presents a series of systemically active galanin receptor 2 selec- tive ligands subsequently evaluated in two different depression-like animal models. Paper 4 investigates a mutated form of human galanin which was found in epilepsy patients and binding and signaling properties of the mutated associ- ated ligand p.(A39E) was examined. In conclusion, this thesis presents the discovery of eight new galanin lig- ands, which can be used to evaluate the galaninergic system as well as to help investigate the possible use of peptides as pharmaceuticals in different diseases. Publications This thesis is based on the following publications 1) Webling, K., Runesson, J., Lang, A., Saar, I., Kofler, B., Langel, Ü., 5 2016. Ala -galanin(2-11) is a GAL2R specific galanin analogue. Neuropeptides, 60, 75-82. 2) Webling, K*., Groves-Chapman, J.L*., Runesson, J., Saar, I., Lang, A., Sillard, R., Jakovenko, E., Kofler, B., Holmes, P.V., Langel, Ü., 2015. Pharmacological stimulation of GAL1R but not GAL2R atten- uates kainic acid-induced neuronal cell death in the rat hippocampus. Neuropeptides, 58, 83-92. 3) Saar, I., Lahe, J., Langel, K., Runesson, J., Webling, K., Järv, J., Rytkönen, J., Närvänen, A., Bartfai, T., Kurrikoff, K., Langel, Ü., 2013. Novel systemically active galanin receptor 2 ligands in de- pression-like behavior. J. Neurochem. 127, 114-123. 4) Guipponi, M., Chentouf, A., Webling, K.E., Freimann, K., Crespel, A., Nobile, C., Lemke, J.R., Hansen, J., Dorn, T., Lesca, G., Ryvlin, P., Hirsch, E., Rudolf, G., Rosenberg, D.S., Weber, Y., Becker, F., Helbig, I., Muhle, H., Salzmann, A., Chaouch, M., Oubaiche, M.L., Ziglio, S., Gehrig, C., Santoni, F., Pizzato, M., Langel, Ü., Anto- narakis, S.E., 2015. Galanin pathogenic mutations in temporal lobe epilepsy. Hum. Mol. Genet. 24, 3082-3091. * These authors contributed equally to the project Additional publications Publications not included in this thesis • Webling, K., Langel, Ü., 2017. Novel peptide based galanin receptor 3 selective antagonists. (Manuscript) • Yu, X., Munoz-Alarcón, A., Ajayi, A., Webling, K.E., Steinhof, A., Langel, Ü., Ström, A.L., 2013. Inhibition of autophagy via p53-mediated disruption of ULK1 in a SCA7 polyglutamine disease model. J. Mol. Neurosci. 50, 586- 599. • Muñoz-Alarcón, A., Helmfors, H., Webling, K., Langel, Ü. 2013. Cell-Penetrating Peptide Fusion Proteins. In: Fusion Protein Technologies for Biopharmaceuticals, (Hoboken, NJ, USA: John Wiley & Sons, Inc.). 397-411. ISBN:978-0-470-64627-4 • Webling, K.E., Runesson, J., Bartfai, T., Langel, Ü., 2012. Galanin receptors and ligands. Front Endocrinol (Lau- sanne). 3:146 • Abela, D., Ritchie, H., Ababneh, D., Gavin, C., Nilsson, M.F., Khan, M. K., Carlsson, K., Webster, W.S. 2010. The effect of drugs with ion channel-blocking activity on the ear- ly embryonic rat heart. Birth Defects Res B Dev Reprod Tox- icol.89, 429-440. This PhD-thesis is an expansion of the work previously presented in my Licentiate thesis, ISBN: 978-91-7649-338-0, where Paper 2 and 3 were included. 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" # $ % < 2 3***. .& "# # 0 %!)= 2 3*********************************. 9 "!'%"!% 44444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444 @9 @ "#'0$(&!%# % !&&!! #1 %(!% 444444444444444444444 @A A !") !&% 4444444444444444444444444444444444444444444444444444444444444444444444444444444444 @C B !$!% 4444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444 A7 Abbreviations 5-HT Serotonin or 5-hydroxytryptamine AC Adenylyl cyclase ACh Acetylcholine ARC Hypothalamic arcuate nucleus BBB Blood-brain barrier BSA Bovine serum albumin cAMP Cyclic adenosine monophosphate CHO Chinese hamster ovary CNS Central nervous system DIC Diisopropylcarbodiimide Dmt 2,6-dimethyl-L-tyrosine DR Dorsal raphe nucleus DRG Dorsal root ganglia ECL Extracellular loop EDTA Ethylenediaminetetraacetic acid EEG Electroencephalography EM Electron microscopy ER Endoplasmic reticulum ERE Estrogen responsive element ESI-MS Electrospray ionization mass spectrometry FAM 5(6)-carboxyfluorescein Fmoc 9-Fluorenylmethyloxycarbonyl GABA Gamma-aminobutyric acid GALP Galanin-like peptide GAL1R Galanin receptor 1 GAL2R Galanin receptor 2 GAL3R Galanin receptor 3 GIRK G protein-regulated inwardly rectifying K+ GPCR G-protein coupled receptor GTP Guanosine triphosphate HEK Human embryonic kidney HPLC High-performance liquid chromatography ICL Intracellular loop i.c.v. Intracerebroventricularly i.p. Intraperitoneal IP Inositol phosphate
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