A number of alpha-melanotropin (α-MSH) analogues have been designed de novo, synthesized and bioassayed at different melanocortin receptors from frog skins, mice and humans. These ligands were designed from two scaffolds, Somatostatin and Deltorphin-II, by two new hybrid approaches, one of which utilizes the modified cyclic structure (H-DPhe-Cys---Cys-Thr-NH₂) of a Somatostatin analogue--Sandostatin®, while the other incorporates the hydrophobic tail of Deltorphin-II (Glu-Val-Val-Gly-NH₂). Some of the ligands designed, H-DPhe-c [XXX-YYY-ZZZ-Arg-Trp-AAA]-Thr-NH₂ [XXX and AAA = Cys, DCys, Pen, DPen; YYY = His, His(1-Me), His(3-Me); ZZZ = Phe and side chain halogen substituted Phe, DPhe, DNal(1') and DNal(2 ')] and c[XXX-YYY-ZZZ-Arg-Trp-Glu]-Val-Val-Gly-NH₂ [XXX = nothing, Gly, β-Ala, γ-Abu, 6-Ahx; YYY = His, His(3-Bom), (S)-cyclopentylglycine (CPG); ZZZ = Phe, DPhe; DNal(2')], show unique selectivity and potency among the receptors tested. In particular, one of the ligands, Delt-38B--c[Gly-CPG-DNal(2')Arg-Trp-Glu]-Val-Val-Gly-NH₂, is a human melanocortin receptor (hMC1R) antagonist (IC₅₀ = 12 nM) the first potent hMC1R antagonist discovered. These results provide strong evidence supporting our hypothesis that ligand scaffolds for different G-protein coupled receptors (GPCRs) can be used to design ligands for other GPCRs. In addition, the structures of some of the ligands have been analyzed by high field solution NMR and their conformation evaluated by modeling with MacroModel. The conformations obtained from these methods help us better understand the structural basis the selectivities and ligand-receptor interactions.
| Identifer | oai:union.ndltd.org:arizona.edu/oai:arizona.openrepository.com:10150/284287 |
| Date | January 2000 |
| Creators | Han, Guoxia |
| Contributors | Hruby, Victor J. |
| Publisher | The University of Arizona. |
| Source Sets | University of Arizona |
| Language | en_US |
| Detected Language | English |
| Type | text, Dissertation-Reproduction (electronic) |
| Rights | Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author. |
Page generated in 0.0017 seconds