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
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.