Long term orexigenic effect of a novel melanocortin 4 receptor selective antagonist

Citation
Gv. Skuladottir et al., Long term orexigenic effect of a novel melanocortin 4 receptor selective antagonist, BR J PHARM, 126(1), 1999, pp. 27-34
Citations number
29
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Pharmacology & Toxicology
Journal title
BRITISH JOURNAL OF PHARMACOLOGY
ISSN journal
0007-1188 → ACNP
Volume
126
Issue
1
Year of publication
1999
Pages
27 - 34
Database
ISI
SICI code
0007-1188(199901)126:1<27:LTOEOA>2.0.ZU;2-3
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 [AcCys(11), dichloro-D-phenylalanine( 14), Cys(18), Asp-NH222]-beta-MSH11-22) showed high affinity (Ki of 0.95 nM ) 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 H S014. 3 HS028 antagonised a alpha-MSH induced increase in cyclic AMP production i n 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 osm otic 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 ca n increase food intake and body weight during chronic administration provid ing further evidence that the MC4 receptor is an important mediator of long term weight homeostasis.