Cyclic Lactam Analogues of Ac-[nle4]α-msh4_11-nh2

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

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33 Scopus citations

Abstract

Two side-chain cyclic lactam analogues of the 4–11 fragment of a-melanocyte-stimulating hormone (a-MSH), Ac-[Nle4,D-Orn5,Glu8]α-MSH4_n-NH2and Ac-[Nle4,D-Orn5,D-Phe7,Glu8]α-MSH4_U-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 a-MSH, Ac-[Nle4]α-MSH4_11-NH2, and Ac-[Nle4,D-Phe7]α-MSH4_u-NH2. in the frog (Ranapipiens) skin bioassay, the L-Phe717-membered ring cyclic analogue was slightly more potent than the linear Ac-[Nle4]α-MSH4_irNH2and exhibited prolonged melanotropic bioactivity (≥4 h). in this same assay, the D-Phe7cyclic analogue was more than 100-fold less potent than the L-Phe cyclic analogue and was 10 000 times less potent than linear Ac-[Nle4,D-Phe7]α-MSH4^11-NH2. in the lizard skin (Anolis carolinensis) bioassay, the L-Phe7cyclic analogue was 100-fold less potent than Ac-[Nle4]a-MSH4_n-NH2, while the D-Phe7cyclic analogue was 10000-fold less potent than both Ac-[Nle4]a-MSH4_n-NH2and the D-Phe7linear derivative Ac-[Nle4,D-Phe7] a-MSH4_n-NH2. The solution conformation of these two cyclic analogues in dimethyl sulfoxide-d6was examined by ID and 2D 500-MHz!H NMR spectroscopy. Our analysis suggests an H bond stabilized C10(or C13) turn for the D-Phe7cyclic structure while the L-Phe7analogue 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
DOIs
StatePublished - Oct 1 1988

ASJC Scopus subject areas

  • Biochemistry

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