January 1999, Volume 126, Issue 1, Pages 27 - 34

Original Article

Long term orexigenic effect of a novel melanocortin 4 receptor selective antagonist Gudrun V. Skuladottir1, Logi Jonsson1, Jon O. Skarphedinsson1, Felikss Mutulis2,4, Ruta Muceniece3,4, Amanda Raine4, Ilze Mutule2,4, Johannes Helgason1, Peteris Prusis4, Jarl E.S. Wikberg4 & Helgi B. Schiöth4,5 1Department of Physiology, University of Iceland, IS-101 Reykjavik, Iceland     2Department of Medicinal Chemistry, Institute of Organic Synthesis, Aizkzaukles 21, LV-1006, Riga, Latvia, Sweden     3Laboratory of Pharmacology, Institute of Organic Synthesis, Aizkzaukles 21, LV-1006, Riga, Latvia, Sweden     4Department of Pharmaceutical Pharmacology, Uppsala University, BMC, Box 591, 751 24 Uppsala, Sweden     5Author for correspondence at: Uppsala University, Department of Pharmaceutical Pharmacology, Biomedical Center, Box 591, 751 24 Uppsala, Sweden. E-mail: helgis@bmc.uu.se.

Keywords

Melanocortin (MC) receptor subtypes;   MSH (melanocyte stimulating hormone);   ligand binding;   cyclic AMP;   HS028;   chronic i.c.v. administration;   food intake

Abstract

1   We designed and synthesized several novel cyclic MSH analogues and tested their affinities for cells expressing the MC1, MC3, MC4 and MC5 receptors. 2   One of the substances HS028 (cyclic [AcCys11, dichloro-D-phenylalanine14, Cys18, Asp-NH222]--MSH11 - 22) showed high affinity (Ki of 0.95nM) and high (80 fold) MC4 receptor selectivity over the MC3 receptor. HS028 thus shows both higher affinity and higher selectivity for the MC4 receptor compared to the earlier first described MC4 receptor selective substance HS014. 3   HS028 antagonised a -MSH induced increase in cyclic AMP production in transfected cells expressing the MC3 and MC4 receptors, whereas it seemed to be a partial agonist for the MC1 and MC5 receptors. 4   Chronic intracerebroventricularly (i.c.v.) administration of HS028 by osmotic minipumps significantly increased both food intake and body weight in a dose dependent manner without tachyphylaxis for a period of 7 days. 5   This is the first report demonstrating that an MC4 receptor antagonist can increase food intake and body weight during chronic administration providing further evidence that the MC4 receptor is an important mediator of long term weight homeostasis.

Received 13 July 1998; Revised 30 September 1998; Accepted 5 October 1998

^© Macmillan Publishers Ltd 1999