Identification and in vivo and in vitro characterization of long acting and melanocortin 4 receptor (MC4-R) selective α-melanocyte-stimulating hormone (α-MSH) analogues

Journal of Medicinal Chemistry
Kilian Conde-FrieboesBirgitte S Wulff

Abstract

We report in vitro and in vivo data of new α-melanocyte-stimulating hormone (α-MSH) analogues which are N-terminal modified with a long chain fatty acid derivative. While keeping the pharmacophoric motif (d-Phe-Arg-Trp) fixed, we tried to improve selectivity and physicochemical parameters like solubility and stability of these analogues by replacing amino acids further away from the motif. Receptor specific changes in binding affinity to the melanocortin receptors were observed between the acetyl derivatives and the fatty acid analogues. Furthermore, amino acids at the N-terminal of α-MSH (Ser-Tyr-Ser) not considered to be part of the pharmacophore were found to have an influence on the MC4/MC1 receptor selectivity. While the acetyl analogues have an in vivo effect for around 7 h, the long chain fatty acid analogues have an effect up to 48 h in an acute feeding study in male Sprague-Dawley rats after a single subcutaneous administration.

References

Sep 1, 1979·Canadian Journal of Biochemistry·M ChrétienN G Seidah
Feb 1, 1986·Neuropeptides·A V VergoniA Bertolini
Oct 1, 1980·Proceedings of the National Academy of Sciences of the United States of America·T K SawyerM E Hadley
Jan 1, 1994·Immunopharmacology·M MousliC Bronner
Jun 1, 1994·Agents and Actions·M Mousli, Y Landry
May 31, 1993·Annals of the New York Academy of Sciences·V J HrubyM E Hadley
Sep 15, 1993·Biochemical and Biophysical Research Communications·V ChhajlaniJ E Wikberg
Oct 1, 1993·Proceedings of the National Academy of Sciences of the United States of America·L Roselli-RehfussR D Cone
Jan 29, 1997·European Journal of Pharmacology·H B SchiöthJ E Wikberg
Aug 12, 1999·European Journal of Pharmacology·J E Wikberg
Jul 21, 2000·The Journal of Clinical Investigation·R D Cone
Aug 22, 2000·Transgenic Research·A S ChenL H Van der Ploeg
Oct 12, 2000·Proceedings of the National Academy of Sciences of the United States of America·L Ste MarieR D Palmiter
Jul 14, 1956·Nature·J I HARRIS, P ROOS
Mar 6, 2004·Pharmacological Reviews·Anna CataniaJames M Lipton
Jun 6, 1931·The Journal of Physiology·U S V Euler, J H Gaddum
Oct 6, 1933·The Journal of Physiology·H C Chang, J H Gaddum
Feb 20, 2008·Photochemistry and Photobiology·Zalfa A Abdel-MalekRenny Starner

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Citations

Nov 10, 2013·The Journal of Endocrinology·Keld FosgerauBirgitte S Wulff
Oct 29, 2013·Journal of Drug Targeting·Xiang Yi, Alexander V Kabanov
Oct 16, 2015·BMC Research Notes·Cathrine Laustrup MøllerBirgitte Schjellerup Wulff
Jul 2, 2014·Cell Metabolism·Beth LuteMarc L Reitman
Apr 9, 2015·Pharmaceutical Patent Analyst·Esther C Y Lee, Philip A Carpino
Jan 21, 2015·Nature·Masoud Ghamari-LangroudiRoger D Cone
May 5, 2016·Nature Communications·Anna SecherJesper V Olsen
Feb 28, 2019·The Journal of Endocrinology·Giulia Baldini, Kevin D Phelan
Aug 16, 2013·Journal of Biomolecular Screening·Stephen L Garland
Mar 9, 2021·Molecular Metabolism·Giles S H YeoRoger A H Adan

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