| De novo design, synthesis, and pharmacology of alpha-melanocyte stimulating hormone analogues derived from somatostatin by a hybrid approach. | |
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MedLine Citation:
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PMID: 14998337 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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A number of alpha-melanotropin (alpha-MSH) analogues have been designed de novo, synthesized, and bioassayed at different melanocortin receptors from frog skin (fMC1R) and mouse/rat (mMC1R, rMC3R, mMC4R, and mMC5R). These ligands were designed from somatostatin by a hybrid approach, which utilizes a modified cyclic structure (H-d-Phe-c[Cys---Cys]-Thr-NH(2)) related to somatostatin analogues (e.g. sandostatin) acting at somatostatin receptors, CTAP which binds specifically to micro opioid receptors, and the core pharmacophore of alpha-MSH (His-Phe-Arg-Trp). Ligands designed were H-d-Phe-c[XXX-YYY-ZZZ-Arg-Trp-AAA]-Thr-NH(2) [XXX and AAA = Cys, d-Cys, Hcy, Pen, d-Pen; YYY = His, His(1'-Me), His(3'-Me); ZZZ = Phe and side chain halogen substituted Phe, d-Phe, d-Nal(1'), and d-Nal(2')]. The compounds showed a wide range of bioactivities at the frog skin MC1R; e.g. H-d-Phe-c[Hcy-His-d-Phe-Arg-Trp-Cys]-Thr-NH(2) (6, EC(50) = 0.30 nM) and H-d-Phe-c[Cys-His-d-Phe-Arg-Trp-d-Cys]-Thr-NH(2) (8, EC(50) = 0.10 nM). In addition, when a lactam bridge was used as in H-d-Phe-c[Asp-His-d-Phe-Arg-Trp-Lys]-Thr-NH(2) (7, EC(50) = 0.10 nM), the analogue obtained is as potent as alpha-MSH in the frog skin MC1R assay. Interestingly, switching the bridge of 6 to give H-d-Phe-c[Cys-His-d-Phe-Arg-Trp-Hcy]-Thr-NH(2) (5, EC(50) = 1000 nM) led to a 3000-fold decrease in agonist activity. An increase in steric size in the side chain of d-Phe(7) reduced the bioactivity significantly. For example, H-d-Phe-c[Cys-His-d-Nal(1')-Arg-Trp-d-Cys]-Thr-NH(2) (24) is 2000-fold less active than 9. On the other hand, H-d-Phe-c[Cys-His-d-Phe(p-I)-Arg-Trp-d-Cys]-Thr-NH(2) (23) lost all agonist activity and became a weak antagonist (IC(50) = 1 x 10(-5) M). Furthermore, the modified CTAP analogues with a d-Trp at position 7 all showed weak antagonist activities (EC(50) = 10(-6) to 10(-7) M). Compounds bioassayed at mouse/rat MCRs displayed intriguing results. Most of them are potent at all four receptors tested (mMC1R, rMC3R, mMC4R, and mMC5R) with poor selectivities. However, two of the ligands, H-d-Phe-c[Cys-His-d-Phe-Arg-Trp-Pen]-Thr-NH(2) (9, EC(50) = 6.9 x 10(-9) M, 6.4 x 10(-8) M, 2.0 x 10(-8) M, and 1.4 x 10(-10) M at mMC1R, rMC3R, mMC4R, and mMC5R, respectively) and H-d-Phe-c[Cys-His(3'-Me)-d-Phe-Arg-Trp-Cys]-Thr-NH(2) (16, EC(50) = 3.5 x 10(-8) M, 3.1 x 10(-8) M, 8.8 x 10(-9) M, and 5.5 x 10(-10) M at mMC1R, rMC3R, mMC4R, and mMC5R, respectively) showed significant selectivities for the mMC5R. Worthy of mention is that neither of these two ligands is potent in the frog skin MC1R assay (EC(50) = 10(-7) M for 9 and EC(50) = 10(-5) M for 16). These results clearly demonstrated that binding behaviors in rodent MCRs are quite different from those in the classical frog skin (R pipiens) assay. |
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Authors:
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Guoxia Han; Carrie Haskell-Luevano; Laura Kendall; Gregg Bonner; Mac E Hadley; Roger D Cone; Victor J Hruby |
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Publication Detail:
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Type: In Vitro; Journal Article; Research Support, U.S. Gov't, P.H.S. |
Journal Detail:
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Title: Journal of medicinal chemistry Volume: 47 ISSN: 0022-2623 ISO Abbreviation: J. Med. Chem. Publication Date: 2004 Mar |
Date Detail:
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Created Date: 2004-03-04 Completed Date: 2004-04-23 Revised Date: 2009-11-19 |
Medline Journal Info:
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Nlm Unique ID: 9716531 Medline TA: J Med Chem Country: United States |
Other Details:
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Languages: eng Pagination: 1514-26 Citation Subset: IM |
Affiliation:
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Departments of Chemistry and Anatomy, University of Arizona, Tucson, Arizona 85721, USA. hruby@u.arizona.edu |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Cysteine / chemistry Drug Design Mice Molecular Conformation Peptides, Cyclic / chemical synthesis*, pharmacology Rana pipiens Rats Receptor, Melanocortin, Type 1 / metabolism Receptor, Melanocortin, Type 3 / metabolism Receptor, Melanocortin, Type 4 / metabolism Receptors, Corticotropin / metabolism Receptors, Melanocortin Skin / metabolism Somatostatin / analogs & derivatives*, chemical synthesis*, pharmacology Structure-Activity Relationship alpha-MSH / analogs & derivatives*, chemical synthesis*, pharmacology |
| Grant Support | |
ID/Acronym/Agency:
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AR-42415/AR/NIAMS NIH HHS; DK-17420/DK/NIDDK NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Peptides, Cyclic; 0/Receptor, Melanocortin, Type 1; 0/Receptor, Melanocortin, Type 3; 0/Receptor, Melanocortin, Type 4; 0/Receptors, Corticotropin; 0/Receptors, Melanocortin; 0/melanocortin 5 receptor; 51110-01-1/Somatostatin; 52-90-4/Cysteine; 581-05-5/alpha-MSH |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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