ISSN:
0006-3525
Keywords:
Chemistry
;
Polymer and Materials Science
Source:
Wiley InterScience Backfile Collection 1832-2000
Topics:
Chemistry and Pharmacology
Notes:
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.
Additional Material:
4 Ill.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1002/bip.360251102
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