The space structures of α‐melanotropin

Nikiforovich, Gregory V.; Shenderovich, Mark D.; Chipens, G. I.

doi:10.1016/0014-5793(81)80236-0

Cited by 13 publications

(5 citation statements)

References 7 publications

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“…The cyclic amide analogues reported here were designed to test a hypothesis recently proposed (Sugg et al, 1986) for a bioactive conformation of the melanotropins. The 5 to 8 cyclization was suggested by computer modeling studies which predicted a salt bridge between the Glu5 and Arg8 side chains (Nikiforovich et al, 1981(Nikiforovich et al, , 1984. In order to promote cyclization and to stabilize the backbone to a left-handed turn, D stereochemistry is required at position 5.…”

Section: Discussionmentioning

confidence: 99%

Cyclic lactam analogs of Ac-[Nle4].alpha.-MSH4-11-NH2

Sugg¹,

Castrucci²,

Hadley³

et al. 1988

Biochemistry

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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)

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Section: Discussionmentioning

confidence: 99%

Cyclic lactam analogs of Ac-[Nle4].alpha.-MSH4-11-NH2

Sugg¹,

Castrucci²,

Hadley³

et al. 1988

Biochemistry

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“…Several computational studies have led to the hypothesis of a bioactive turn conformation in melanocortin peptides localized in the conserved message sequence His‐Phe‐Arg‐Trp (22–25). In support of the bioactive turn hypothesis, cyclic analogs of α ‐MSH (Ac‐Ser‐Tyr‐Ser‐Met‐Glu‐His‐Phe‐Arg‐Trp‐Gly‐Lys‐Pro‐Val‐NH 2 ) and NDP‐MSH (Ac‐Ser‐Tyr‐Ser‐Nle‐Glu‐His‐ d ‐Phe‐Arg‐Trp‐Gly‐Lys‐Pro‐Val‐NH 2 ), such as MTII (Ac‐Nle‐c[Asp‐His‐ d ‐Phe‐Arg‐Trp‐Lys]‐NH 2 ; 26,27) and related compounds (Ac‐Nle‐c[Asp‐Pro‐ d ‐Phe‐Arg‐Trp‐Lys]‐NH 2 ), have exhibited enhanced potency, selectivity, and/or prolonged duration of action (28–31).…”

Section: Analytical Data For the Peptides Tested In This Studyamentioning

confidence: 99%

Aza‐scanning of the Potent Melanocortin Receptor Agonist Ac‐His‐d‐Phe‐Arg‐Trp‐NH₂

et al. 2006

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The melanocortin pathway is an important participant in the regulation of skin pigmentation, steroidogenesis, obesity, energy homeostasis, and exocrine gland function. Melanocortin agonists contain the putative sequence 'His-Phe-Arg-Trp', which has been designated as the 'message' sequence for melanocortin peptides, and this sequence has been hypothesized to adopt a bioactive reverse turn conformation. Exploring the relationship between its structure and biological activity, we report the synthesis and evaluation of seven aza-analogs of the potent melanocortin receptor agonist Ac-His-D-Phe-Arg-Trp-NH 2 . Azaamino acids, in which the a-carbon was replaced by nitrogen, were inserted along the peptide sequence to probe the importance of local configuration and turn conformation on the biology of this tetrapeptide. Although systematic substitution of azaamino acids for the D-Phe and Arg residues led to a significant loss of activity relative to the parent peptide for all melanocortin receptor subtypes examined, substitution of aza-amino acids at the C-terminal Trp residue gave analogs equipotent to the parent peptide. In summary, the aza-scan has demonstrated that recognition of this tetrapeptide by the melanocortin receptors is particularly sensitive to modifications of configuration and conformation at the D-Phe and Arg residues versus the Trp amino acid. In light of aza-residues imparting resistance from enzymatic degradation, C-terminal aza-amino acid analogs may be used to design new peptide mimics with enhanced metabolic stability.

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“…54,55,58,59 The time histories of the distances between all pairs of the positively charged nitrogens on the end of the Arg 8 side chain, and the negatively charged oxygens on the end of the Glu 5 side chain were monitored and one pair is displayed in Figure 5e. From initial distances of 16 -19 Å for the various pairs, these distances fall to less that 3 Å within the first 5 ns of the simulation, indicating a close contact between these two side chains.…”

Section: Figurementioning

confidence: 99%

“…66 Another interesting question about the conformation of ␣-MSH is whether the biologically active structure is stabilized by a salt bridge. Two possible salt bridges have been proposed, one 54,55,58,59 involving the electrostatically charged side chains of Glu 5 and Arg 8 and the other 1,44 involving Glu 5 and Lys 11 . Experiments based on structure-activity studies have not been conclusive, first on whether a salt bridge does exist and second on the importance of these charged moieties for the potency of this peptide.…”

mentioning

confidence: 99%

Structure and dynamics of ?-MSH using DRISM integral equation theory and stochastic dynamics

Prabhu¹,

Perkyns²,

Pettitt³

et al. 1999

Biopolymers

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The space structures of α‐melanotropin

Cited by 13 publications

References 7 publications

Cyclic lactam analogs of Ac-[Nle4].alpha.-MSH4-11-NH2

Cyclic lactam analogs of Ac-[Nle4].alpha.-MSH4-11-NH2

Aza‐scanning of the Potent Melanocortin Receptor Agonist Ac‐His‐d‐Phe‐Arg‐Trp‐NH₂

Structure and dynamics of ?-MSH using DRISM integral equation theory and stochastic dynamics

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The space structures of α‐melanotropin

Cited by 13 publications

References 7 publications

Cyclic lactam analogs of Ac-[Nle4].alpha.-MSH4-11-NH2

Cyclic lactam analogs of Ac-[Nle4].alpha.-MSH4-11-NH2

Aza‐scanning of the Potent Melanocortin Receptor Agonist Ac‐His‐d‐Phe‐Arg‐Trp‐NH2

Structure and dynamics of ?-MSH using DRISM integral equation theory and stochastic dynamics

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Aza‐scanning of the Potent Melanocortin Receptor Agonist Ac‐His‐d‐Phe‐Arg‐Trp‐NH₂