Cyclic lactam analogues of Ac-[Nle4]α-MSH4-11-H2

Elizabeth E. Sugg, Ana Maria Ana, Mac E. Hadley, Georges Van Binst, Victor J Hruby

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Abstract

Two side-chain cyclic lactam analogues of the 4-11 fragment of α-melanocyte-stimulating hormone (α-MSH), Ac-[Nle4,D-Orn5,Glu8]α-MSH 4-11-NH2 and Ac-[Nle4,D-Orn5,D-Phe7,Glu 8]α-MSH4-11-NH2, were prepared on p-methylbenzhydrylamine resin by using a combination of Nα-Boc and Nα-Fmoc synthetic strategies with diphenyl phosphorazidate mediated cyclization. The melanotropin activities of these two analogues were examined and compared relative to those of α-MSH, Ac-[Nle4]α-MSH4-11-NH2, and Ac-[Nle4,D-Phe7]α-MSH4-11-NH2. In the frog (Rana pipiens) skin bioassay, the L-Phe7 17-membered ring cyclic analogue was slightly more potent than the linear Ac-[Nle4]α-MSH4-11-NH2 and exhibited prolonged melanotropic bioactivity (≥4 h). In this same assay, the D-Phe7 cyclic analogue was more than 100-fold less potent than the L-Phe cyclic analogue and was 10000 times less potent than linear Ac-[Nle4,D-Phe7]α-MSH4-11-NH2. In the lizard skin (Anolis carolinensis) bioassay, the L-Phe7 cyclic analogue was 100-fold less potent than Ac-[Nle4]α-MSH4-11-NH2, while the D-Phe7 cyclic analogue was 10000-fold less potent than both Ac-[Nle4]α-MSH4-11-NH2 and the D-Phe7 linear derivative Ac-[Nle4,D-Phe7]α-MSH4-11-NH2. The solution conformation of these two cyclic analogues in dimethyl sulfoxide-d6 was examined by 1D and 2D 500-MHz 1H NMR spectroscopy. Our analysis suggests an H bond stabilized C10 (or C13) turn for the D-Phe7 cyclic structure while the L-Phe7 analogue is more conformationally flexible. More importantly, these results suggest that melanotropic potency may be correlated with a close spatial relationship between the side chains of His6, Phe7, and Trp9.

Original languageEnglish (US)
Pages (from-to)8181-8188
Number of pages8
JournalBiochemistry
Volume27
Issue number21
Publication statusPublished - 1988

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ASJC Scopus subject areas

  • Biochemistry

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Sugg, E. E., Ana, A. M., Hadley, M. E., Van Binst, G., & Hruby, V. J. (1988). Cyclic lactam analogues of Ac-[Nle4]α-MSH4-11-H2. Biochemistry, 27(21), 8181-8188.