Discovery of novel melanocortin 4 receptor selective MSH analogues

We synthesized a novel series of cyclic melanocyte stimulating hormone (MSH) analogues and tested their binding properties on cells transiently expressing the human melanocortin 1 (MC 1 ), MC 3 , MC 4 and MC 5 receptors. We discovered that compounds with 26 membered rings of [Cys 4 , D ‐Nal 7 ,Cys 11 ]α‐MSH(4–11) displayed specific MC 4 receptor selectivity. The preference order of the different MC receptor subtypes for the novel [Cys 4 D ‐Nal 7 Cys 11 ]α‐MSH(4–11) analogues are distinct from all other known MSH analogues, particularly as they bind the MC 4 receptor with high and the MC 1 receptor with low relative affinities. HS964 and HS014 have 12 and 17 fold MC 4 /MC 3 receptor selectivity, respectively, which is much higher than for the previously described cyclic lactam and [Cys 4 ,Cys 10 ]α‐MSH analogues SHU9119 and HS9510. HS964 is the first substance showing higher affinity for the MC 5 receptor than the MC 1 receptor. HS014, which was the most potent and selective MC 4 receptor ligand ( K i 3.2 n M , which is ∼300 fold higher affinity than for α‐MSH), was also demonstrated to antagonize α‐MSH stimulation of cyclic AMP in MC 4 receptor transfected cells. We found that a compound with a 29 membered ring of [Cys 3 ,Nle 10 , D ‐Nal 7 ,Cys 11 ]α‐MSH(3–11) (HS010) had the highest affinity for the MC 3 receptor. This is the first study to describe ligands that are truly MC 4 selective and a ligand having a high affinity for the MC 3 receptor. The novel compounds may be of use in clarifying the physiological roles of the MC 3 , MC 4 and MC 5 receptors.