Discovery of novel melanocortin₄ receptor selective MSH analogues

Abstract

1. We synthesized a novel series of cyclic melanocyte stimulating hormone (MSH) analogues and tested their binding properties on cells transiently expressing the human melanocortin₁ (MC₁), MC₃, MC₄ and MC₅ receptors.

2. We discovered that compounds with 26 membered rings of [Cys⁴,D-Nal⁷,Cys¹¹]α-MSH(4–11) displayed specific MC₄ receptor selectivity. The preference order of the different MC receptor subtypes for the novel [Cys⁴D-Nal⁷Cys¹¹]α-MSH(4–11) analogues are distinct from all other known MSH analogues, particularly as they bind the MC₄ receptor with high and the MC₁ receptor with low relative affinities.

3. HS964 and HS014 have 12 and 17 fold MC₄/MC₃ receptor selectivity, respectively, which is much higher than for the previously described cyclic lactam and [Cys⁴,Cys¹⁰]α-MSH analogues SHU9119 and HS9510.

4. HS964 is the first substance showing higher affinity for the MC₅ receptor than the MC₁ receptor.

5. HS014, which was the most potent and selective MC₄ receptor ligand (K_i 3.2 nM, which is ∼300 fold higher affinity than for α-MSH), was also demonstrated to antagonize α-MSH stimulation of cyclic AMP in MC₄ receptor transfected cells.

6. We found that a compound with a 29 membered ring of [Cys³,Nle¹⁰,D-Nal⁷,Cys¹¹]α-MSH(3–11) (HS010) had the highest affinity for the MC₃ receptor.

7. This is the first study to describe ligands 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.

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