Analogs of Ac‐[Nle4]‐α‐MSH4–11‐NH2 and Ac‐[Nle4, D‐Phe7]‐α‐MSH4–11‐NH2 were prepared with D‐isomeric replacements at the His6, Arg8, and Trp9 residues. The requirement for an indole moiety at position 9 also was evaluated by replacement with L‐leucine in both parent fragment analogs. D‐isomeric replacements at positions 6 and 8 in either series were detrimental to biological potency in frog (Rana pipiens) and lizard skin (Anolis carolinensis) in vitro melanotropic assays. However, Ac‐[Nle4, D‐Trp9]‐α‐MSH4–11‐NH2 and Ac‐[Nle4, D‐Phe7, D‐Trp9]‐α‐MSH4–11‐NH2 were equipotent and 10 × more potent than Ac‐[Nle4]‐α‐MSH4–11‐NH2, respectively, in the lizard skin bioassay, and 30 and 1900 times more potent in the frog skin bioassay. Ac‐[Nle4, D‐Phe7, D‐Trp9]‐α‐MSH4–11‐NH2 was 3 × more potent than α‐MSH in the frog skin bioassay. Proton nmr studies in aqueous solution revealed a marked preservation of the backbone conformation of these linear analogs. Chemical‐shift variations due to the through‐space anisotropic influence of the core aromatic amino acid residues permitted evaluation of side‐chain topology. The observed topology was consistent with nonhydrogen‐bonded β‐like structure (ϕ = −139°, ψ = +135° for L‐amino acids; ϕ = +139°, ψ = −135° for D‐amino acids) as the predominant solution conformation. The biological and conformational data suggest that high melanotropic potency requires a close spatial arrangement of the His6, Phe7, and Arg8 side chains.
ASJC Scopus subject areas
- Organic Chemistry