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 melanocortin 1 (MC 1 ), MC 3 , MC 4 and MC 5 receptors. 2 We discovered that compounds with 26 membered rings of [Cys 4 ,D-Nal 7 ,Cys 11 ]a-MSH(4 ± 11) displayed speci®c MC 4 receptor selectivity. The preference order of the di erent MC receptor subtypes for the novel [Cys 4 D-Nal 7 Cys 11 ]a-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 a nities. 3 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 ]a-MSH analogues SHU9119 and HS9510. 4 HS964 is the ®rst substance showing higher a nity for the MC 5 receptor than the MC 1 receptor. 5 HS014, which was the most potent and selective MC 4 receptor ligand (K i 3.2 nM, which is *300 fold higher a nity than for a-MSH), was also demonstrated to antagonize a-MSH stimulation of cyclic AMP in MC 4 receptor transfected cells. 6 We found that a compound with a 29 membered ring of [Cys 3 ,Nle 10 ,D-Nal 7 ,Cys 11 ]a-MSH(3 ± 11) (HS010) had the highest a nity for the MC 3 receptor. 7 This is the ®rst study to describe ligands that are truly MC 4 selective and a ligand having a high a nity 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.

Structure–activity studies of new melanocortin peptides containing an aromatic amino acid at the N-terminal position

“…These modifications have suggested that amino acid residues at the 6 (His), 7 (Phe), 8 (Arg), and 9 (Trp) positions are important for molecular recognition and activation of the melanocortin receptors. In particular, positions 6 and 7 of cyclic and of linear derivatives of α-MSH appeared to be important for high affinity and selectivity at hMC3 and hMC4 receptors [1,17,26,36,39,41].…”

Conformation of the Core Sequence in Melanocortin Peptides Directs Selectivity for the Melanocortin MC3 and MC4 Receptors

“…, and Phe 12 of ␥-MSH, Schioth et al (39) suggested that the ␥-MSH C terminus hinders MC4R binding. However, this peptide showed an equal loss of affinity for the MC3R.…”

Repeated agouti related peptide (83–132) injections inhibit cocaine-induced locomotor sensitisation, but not via the nucleus accumbens

“…SHU9119 is a potent melanocortin MC 3 and melanocortin MC 4 receptor antagonist with IC50 values of 1.2 and 0.36 nM respectively (Schioth et al, 1998). AgRP is an inverse agonist that binds with similar affinities to melanocortin MC 3 and melanocortin MC 4 receptors (K i ¼3.3 and 2.6 nM respectively (Yang et al, 1999)).…”