D-Isomeric replacements within the 6–9 core sequence of ac-[Nle4]-α-MSH4–11-NH2: A topological model for the solution conformation of α-melanotropin
✍ Scribed by Elizabeth E. Sugg; Wayne L. Cody; Zalfa Abdel-Malek; Mac E. Hadley; Victor J. Hruby
- Book ID
- 102761161
- Publisher
- Wiley (John Wiley & Sons)
- Year
- 1986
- Tongue
- English
- Weight
- 809 KB
- Volume
- 25
- Category
- Article
- ISSN
- 0006-3525
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✦ Synopsis
Analogs of Ac-[Nle4]-cr-MSH4.,,-NH2 and Ac-[Nle4, D -P ~~~] -~-M S H ~. , , -N H ~ were prepared with D-kOtneriC replacements at the His', Arg', and Trpg 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 ( R a m pipiens) and lizard skin ( A n o h carolinensis) in vitro melanotropic assays. However, Ac-[Nle4, D-Trpg]-cr-MSH4~,,-NH2 and Ac-[Nle4, ~-P h e ~, D-Trps]1-a-MSH,,,-NH2 were equipotent and 10 X more potent than Ac-[Nle4]-a-MSH4.,,-NH,, respectively, in the lizard skin bioassay, and 30 and 1900 times more potent in the frog skin bioassay.
Ac-[Nle4,~-Phe7,~-Trps]-a-MSH4.,,-NH2 was 3 X more potent than a-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 B-like structure (# = -139O, + = +135" for L--O acids; 6 = +139", + = -135O 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 Args side chains.