376 research outputs found
Preparation of 'side-chain-to-side-chain' cyclic peptides by Allyl and Alloc strategy: Potential for library synthesis
No full textAutomated and manual deprotection methods for allyl/allyloxycarbonyl (Allyl/Alloc) were evaluated for the prepn. of side-chain-to-side-chain cyclic peptides. Using a std. Allyl/Alloc deprotection method, a small library of cyclic peptides with lactam bridges (with seven amino acids) was prepd. on an automatic peptide synthesizer. We demonstrate that the Guibe method for removing Allyl/Alloc protecting groups under specific neutral conditions [Pd(PPh3)4/PhSiH3/DCM] can be a useful, efficient and reliable method for prepg. long cyclic peptides on a resin. We have also manually synthesized a cyclic glucagon analog contg. 24 amino acid residues. These results demonstrated that properly controlled palladium-mediated deprotection of Allyl/Alloc protecting groups can be used to prep. cyclic peptides on the resin using an automated peptide synthesizer and cyclic peptides with a long chain
Substitution of Arginine with Proline and Proline Derivatives in MSH Leads to Selectivity for Human Melanocortin 4 Receptor (hMC4R)
No full textStructure-activity studies of new melanocortin peptides containing an aromatic amino acid at the N-terminal position
No full text
Structure-Activity Relationships of alpha-MSH Analogues at the Human Melanocortin MC3, MC4, and MC5 Receptors. Discovery of Highly Selective hMC3R, hMC4R, and hMC5R Analogues.
No full textIt 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 R-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 ç-MSH, two
different series of ç-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 ç-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-NH2 with Gly4) is more important for selectivity.
The 2nd series is made of D-2-naphthylalanine (D-Nal(2¢)) scan of the ç-MSH sequence at
position 6 and 8 and the replacement of His5 with Pro (analogue 13). Analogue 12, H-Tyr-Val-
Nle-Gly-His-Phe-Arg-D-Nal(2¢)-Asp-Arg-Phe-Gly-NH2, 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-NH2,
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-NH2, 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
Structure-Activity Relationships of Novel Cyclic alpha-MSH/gamma-MSH Hybrid Analogues which Lead to Potent and Selective Ligands for the Human MC3R and Human MC5R
No full textConformational study on cyclic melanocortin ligands and new insight into their binding mode at the MC4 receptor
No full textThe melanocortin receptors are involved in many physiological functions, including pigmentation, sexual function, feeding behavior, and energy homeostasis, making them potential targets to treat obesity, sexual dysfunction, etc. Understanding the basis of the ligand-receptor interactions is crucial for the design of potent and selective ligands for these receptors. The conformational preferences of the cyclic melanocortin ligands MTII (Ac-Nle(4)-c[Asp(5)-His(6)-DPhe(7)-Arg(8)-Trp(9)-Lys(10)]-NH(2)) and SHU9119 (Ac-Nle(4)-c[Asp(5)-His(6)-DNal(2')(7)-Arg(8)-Trp(9)-Lys(10)]-NH(2)), which show agonist and antagonist activity at the h-MC4R, respectively, were comprehensively investigated by solution NMR spectroscopy in different environments. In particular, water and water/DMSO (8:2) solutions were used as isotropic solutions and an aqueous solution of DPC (dodecylphosphocholine) micelles was used as a membrane mimetic environment. NMR-derived conformations of these two ligands were docked within h-MC4R models. NMR and docking studies revealed intriguing differences which can help explain the different activities of these two ligand
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