Cyclic lactam analogues of Ac-[Nle4]alpha-MSH4-11-NH2.
Two side-chain cyclic lactam analogues of the 4-11 fragment of alpha-melanocyte-stimulating hormone (alpha-MSH), Ac-[Nle4,D-Orn5,Glu8]alpha-MSH4-11-NH2 and Ac-[Nle4,D-Orn5,D-Phe7,Glu8]alpha-MSH4-11-NH2, were prepared on p-methylbenzhydrylamine resin by using a combination of N alpha-Boc and N alpha-Fmoc synthetic strategies with diphenyl phosphorazidate mediated cyclization. The melanotropin activities of these two analogues were examined and compared relative to those of alpha-MSH, Ac-[Nle4]alpha-MSH4-11-NH2, and Ac-[Nle4,D-Phe7]alpha-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]alpha-MSH4-11-NH2 and exhibited prolonged melanotropic bioactivity (greater than or equal to 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 10,000 times less potent than linear Ac-[Nle4,D-Phe7]alpha-MSH4-11-NH2. In the lizard skin (Anolis carolinensis) bioassay, the L-Phe7 cyclic analogue was 100-fold less potent than Ac-[Nle4]alpha-MSH4-11-NH2, while the D-Phe7 cyclic analogue was 10,000-fold less potent than both Ac-[Nle4]alpha-MSH4-11-NH2 and the D-Phe7 linear derivative Ac-[Nle4,D-Phe7]alpha-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.(ABSTRACT TRUNCATED AT 250 WORDS)
Sugg
E E
EE
Department of Chemistry, University of Arizona, Tucson 85721.
Castrucci
A M
AM
Hadley
M E
ME
van Binst
G
G
Hruby
V J
VJ
D000818:Animals; D015195:Drug Design; D007202:Indicators and Reagents; D008116:Lizards; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008958:Models, Molecular; D011487:Protein Conformation; D011894:Rana pipiens; D012867:Skin / Q000187:drug effects; D013329:Structure-Activity Relationship; D000521:alpha-MSH / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*
D007202:Indicators and Reagents; C058932:alpha-MSH (4-11)NH2, Ac-Nle(4)-Orn(5)-Glu(8)-; C058933:alpha-MSH(4-11)NH2, Ac-Nl4(4)-Orn(5)-Phe(7)-Glu(8)-; D000521:alpha-MSH