NMR and quenched molecular dynamics studies of superpotent linear and cyclic α-melanotropins

Conformational searching, computer simulations, synthesis and NMR are used on a variety of α melanocyte‐stimulating hormone (α‐MSH) analogues to understand the physical characteristics required for biological potency. Peptides I (AC‐[Nle4,Asp5,d‐Phe7,Lys10]α‐MSH(4‐10)‐NH2), II (Ac‐c[Nle4,Asp5,d‐Phe7,Lys10]α‐MSH(4‐10)‐NH2) and III (Ac‐[Nle4,Asp5,d‐Phe7,Dap10]α‐MSH(4‐10)‐NH2 all show very similar conformational properties (backbone and side‐chain torsional angles), and all display high biological potencies. The modeling results for these compounds are supported by the NMR data. Peptide IV (Ac‐c[Nle4,Asp5,d‐Phe7,Dap10]α‐MSH(4‐10)‐NH2) appears to have a markedly different conformation and has decreased biological potency.