Selectivity of cyclic [D-Nal⁷] and [D-Phe⁷] substituted MSH analogues for the melanocortin receptor subtypes

The binding of the 2 cyclic lactam MSH (4-10) analogues (MTII, SHU9119), and 5 cyclic [Cys⁴, Cys¹⁰]α-MSH analogues were tested on cells transiently expressing the human MC1, MC3, MC4 and MC5 receptors. The results indicate a differential importance of the C-terminal (Lys-Pro-Val) and N-terminal (Ser-Tyr-Ser) of cyclic [Cys⁴, Cys¹⁰]α-MSH analogues in binding to the MC receptor subtypes. Substitution of D-Phe⁷ by D-Nal(2')⁷ in both the cyclic lactam MSH (4-10) and the cyclic disulphide MSH (4-10) analogues resulted in a shift in favour of selectivity for the MC4 receptor; the disulphide analogue, [Cys⁴, D-Nal(2')⁷ Cys¹⁰]α-MSH (4-10) (HS9510), showing the highest selectivity for the MC4 receptor among all the substances tested. However, the cyclic lactams displayed an over all higher affinity for the MC receptors, than any of the cyclic disulphide MSH (4-10) analogues.