DISCOVERY OF NOVEL MELANOCORTIN(4) RECEPTOR-SELECTIVE MSH ANALOGS

1 We synthesized a novel series of cyclic melanocyte stimulating hormo ne (MSH) analogues and tested their binding properties on cells transi ently expressing the human melanocortin(1) (MC1), MC3, MC4 and MC5 rec eptors. 2 We discovered that compounds with 26 membered rings of [Cys( 4),D-Nal(7),Cys(11)]alpha-MSH(4-11) displayed specific MC4 receptor se lectivity. The preference order of the different MC receptor subtypes for the novel [Cys(4)D-Nal(7)Cys(11)]alpha-MSH(4-11) analogues are dis tinct from all other known MSH analogues, particularly as they bind th e MC4 receptor with high and the MC1 receptor with low relative affini ties. 3 HS964 and HS014 have 12 and 17 fold MC4/MC3 receptor selectivi ty, respectively, which is much higher than for the previously describ ed cyclic lactam and [Cys(4),Cys(10)]alpha-MSH analogues SHU9119 and H S9510. 4 HS964 is the first substance showing higher affinity for the MCS receptor than the MC1 receptor. 5 HS014, which was the most potent and selective MC5 receptor ligand (K-i 3.2 nM, which is similar to 30 0 fold higher affinity than for alpha-MSH), was also demonstrated to a ntagonize alpha-MSH stimulation of cyclic AMP in MC4 receptor transfec ted cells. 6 We found that a compound with a 29 membered ring of [Cys( 3),Nle(10),D-Nal(7),Cys(11)]alpha-MSH(3-11) (HS010) had the highest af finity for the MC3 receptor. 7 This is the first study to describe lig ands that are truly MC4 selective and a ligand having a high affinity for the MC3 receptor. The novel compounds may be of use in clarifying the physiological roles of the MC3, MC4 and MC5 receptors.