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.

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 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

Proton n.m.r. investigation of conformational influence of penicillamine residues on the disulfide ring system of opioid receptor selective Somatostatin derivatives

Three cyclic disulfide analogs related to somatostatin, d‐Phe1 ‐Cys2‐Tyr3‐d‐Trp4‐Lys5‐Thr6‐Xxx7‐Thr8NH2 (where Xxx =l‐Pen 1; l‐Cys 3; or d‐Pen 4) were examined in DMSO‐d6 by one‐ and two‐dimensional proton n.m.r. spectroscopy in order to analyze the conformational influence of the position‐7 residue on the 20‐membered disulfide ring. From these studies it was concluded that all three analogs maintain a β II turn solution conformation for the core tetrapeptide‐Tyr3‐d‐Trp4‐Lys5‐Thr6‐. However, the disulfide conformation differs in the analogs, with 1 and 3 having a left‐handed and 4 a right‐handed disulfide chirality. Copyright © 1988, Wiley Blackwell. All rights reservedSCOPUS: ar.jinfo:eu-repo/semantics/publishe

Cholecystokinic activity of N alpha-hydroxysulfonyl-[Nle28,31]CCK26-33 analogues modified at the C-terminal residue.

Three new analogues of N alpha-hydroxysulfonyl-[Nle28,31]CCK26-33 are reported in which the C-terminal L-Phe33 residue has been replaced by L-Leu, D-Phe or N-methyl-L-Phe. Biological evaluation in a series of binding and bioassays demonstrates that both L-stereochemistry and an aromatic side chain at position-33 are essential for full agonist activity. While the L-Leu33 and D-Phe33 analogues had reduced potencies in stimulating contraction of the guinea pig ileum or gall bladder, the D-Phe33 analogue was fourfold selective for the ileum. This latter analogue also exhibited apparent partial agonism in the rat pancreatic amylase release assay. The N-methyl-L-Phe33 analogue was almost equipotent to the parent analogue in all bioassays, suggesting that this modification might be useful for introducing enzymatic stability in CCK analogues