Structure-function relationships of the melanotropins

Yajima, Haruaki; Kiso, Yoshiaki

doi:10.1016/0306-039x(75)90052-5

Cited by 1 publication

(2 citation statements)

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“…This core sequence is the minimal fragment essential for biological activity 14,15 and is believed to form the pharmacophore. [14][15][16][17] Furthermore, the "bioactive conformation" of R-MSH was first shown to possibly exist as a reverse-turn-type conformation at this His-Phe-Arg-Trp sequence by the design of the macrocyclic analogue c[Cys 4 ,Cys 10 ]-R-MSH, a superagonist in the frog skin bioassay 18 based on the results from the linear analogue Ac-[Nle, 4 D-Phe 7 ]-R-MSH. 19 Thus, to probe the receptor-active conformation of this pharmacophore in γ-MSH, we have carried out a cyclic scan (Series 1, Table 2).…”

Section: Introductionmentioning

confidence: 99%

“…As shown before, all the melanotropins are characterized by the core or central tetrapeptide sequence, His-Phe-Arg-Trp, flanked by N - and C -terminal residues. This core sequence is the minimal fragment essential for biological activity , and is believed to form the pharmacophore. − Furthermore, the “bioactive conformation” of α-MSH was first shown to possibly exist as a reverse-turn-type conformation at this His-Phe-Arg-Trp sequence by the design of the macrocyclic analogue c [Cys 4 ,Cys 10 ]-α-MSH, a superagonist in the frog skin bioassay based on the results from the linear analogue Ac-[Nle, d -Phe 7 ]-α-MSH ).…”

Section: Introductionmentioning

confidence: 99%

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Structure−Activity Relationships of γ-MSH Analogues at the Human Melanocortin MC3, MC4, and MC5 Receptors. Discovery of Highly Selective hMC3R, hMC4R, and hMC5R Analogues

et al. 2003

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It has been shown by extensive studies that melanotropin bioactivities are critically dependent on the core or central tetrapeptide sequence, His-Phe-Arg-Trp, and in alpha-MSH it has been demonstrated further that a reverse-turn type conformation exists at this pharmacophore. To probe the receptor active conformation of the pharmacophore His-Phe-Arg-Trp in gamma-MSH, two different series of gamma-MSH analogues have been designed and synthesized and their biological activities determined at hMC3R, hMC4R, and hMC5R. The 1st series consists of a cyclic scan using different disulfides or lactam bridges. It was found that cyclization of the native gamma-MSH around the highly conserved sequence can lead to shifts in affinity and selectivity for hMC4R instead of the hMC3R as seen in the native peptide. Furthermore, a 23-membered ring is desirable for potency (e.g., analogues 6 and 10) whereas a 26-membered ring (analogue 1, H-Tyr-Val-c[Cys-Gly-His-Phe-Arg-Trp-Cys]-Arg-Phe-Gly-NH(2) with Gly(4)) is more important for selectivity. The 2nd series is made of d-2-naphthylalanine (d-Nal(2')) scan of the gamma-MSH sequence at position 6 and 8 and the replacement of His(5) with Pro (analogue 13). Analogue 12, H-Tyr-Val-Nle-Gly-His-Phe-Arg-d-Nal(2')-Asp-Arg-Phe-Gly-NH(2), is a potent and selective antagonist at the hMC4R, and analogue 15, H-Tyr-Val-Nle-Gly-Aib-Phe-Arg-d-Nal(2')-Asp-Arg-Phe-Gly-NH(2), is a highly selective and potent agonist of the hMC5R. A most promising analogue is 13, H-Tyr-Val-Nle-Gly-Pro-d-Nal(2')-Arg-Trp-Asp-Arg-Phe-Gly-NH(2), which is a very potent agonist of the hMC4R, and this analogue can be further evaluated for feeding behavior and the regulation of fat stores.

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