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

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 N^α-Boc and N^α-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.