Discovery of novel melanocortin4 receptor selective MSH analogues

British Journal of Pharmacology
H B SchiöthJ E Wikberg

Abstract

1. We synthesized a novel series of cyclic melanocyte stimulating hormone (MSH) analogues and tested their binding properties on cells transiently expressing the human melanocortin1 (MC1), MC3, MC4 and MC5 receptors. 2. We discovered that compounds with 26 membered rings of [Cys4,D-Nal7,Cys11]alpha-MSH(4-11) displayed specific MC4 receptor selectivity. The preference order of the different MC receptor subtypes for the novel [Cys4D-Nal7Cys11]alpha-MSH(4-11) analogues are distinct from all other known MSH analogues, particularly as they bind the MC4 receptor with high and the MC1 receptor with low relative affinities. 3. HS964 and HS014 have 12 and 17 fold MC4/MC3 receptor selectivity, respectively, which is much higher than for the previously described cyclic lactam and [Cys4,Cys10]alpha-MSH analogues SHU9119 and HS9510. 4. HS964 is the first substance showing higher affinity for the MC5 receptor than the MC1 receptor. 5. HS014, which was the most potent and selective MC4 receptor ligand (Ki 3.2 nM, which is approximately 300 fold higher affinity than for alpha-MSH), was also demonstrated to antagonize alpha-MSH stimulation of cyclic AMP in MC4 receptor transfected cells. 6. We found that a compound with a 29 membered ring of [C...Continue Reading

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Citations

Dec 9, 2003·European Journal of Pharmacology·Sara BellasioAngelo Reggiani
May 20, 2004·European Urology·William J Martin, D Euan MacIntyre
Jul 16, 2013·Progress in Neurobiology·Antonio Argiolas, Maria Rosaria Melis
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Aug 12, 2003·European Journal of Pharmacology·Shigeyuki ChakiShigeru Okuyama
Apr 16, 1999·European Journal of Pharmacology·A V VergoniH B Schiöth
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Jan 22, 2000·Neuroscience and Biobehavioral Reviews·A Argiolas
Mar 14, 2002·Brain Research. Brain Research Reviews·Helgi B Schiöth, Hajime Watanobe
Jun 6, 2002·Regulatory Peptides·Helgi B SchiöthDan Larhammar
Apr 2, 2003·Peptides·Wouter A J NijenhuisRoger A H Adan
Jun 7, 2000·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·A V VergoniA Bertolini
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Dec 6, 2005·Peptides·Andrea Beatríz CragnoliniTeresa Nieves Scimonelli
Sep 13, 2005·Journal of Neuroimmunology·Ruta MucenieceMaija Dambrova

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