Structure–Activity Relationships of the Tetrapeptide Ac-His-Arg-(pI)DPhe-Tic-NH2 at the Mouse Melanocortin Receptors: Modification at the (pI)DPhe Position Leads to mMC3R Versus mMC4R Selective Ligands
Abstract
:1. Introduction
2. Results
Peptide Synthesis and Pharmacological Evaluation
3. Discussion
4. Materials and Methods
4.1. Reagents
4.2. Peptide Synthesis
4.3. AlphaScreen Bioassay
4.4. β-Galactosidase Assay
4.5. Data Analysis
5. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Sample Availability: Samples of the compounds are available from the authors. |
Peptide | Sequence | Retention Time (min) | M (Calculated) | M + H (Observed) | Purity (%) | |
---|---|---|---|---|---|---|
System 1 | System 2 | |||||
KNS2-153 | Ac-His-DPhe-Arg-Trp-NH2 | 10.1 | 15.6 | 685.3 | 686.4 | >98 |
KNS2-22-4 | Ac-His-Arg-(pI)DPhe-Tic-NH2 | 14.9 | 23.6 | 784.2 | 785.3 | >97 |
KNS2-22-3 | Ac-His-Arg-(pBr)DPhe-Tic-NH2 | 14.9 | 23.2 | 736.3, 738.3 b | 737.3, 739.3 b | >98 |
KNS2-22-1 | Ac-His-Arg-(pCl)DPhe-Tic-NH2 | 14.6 | 22.7 | 692.3 | 693.5 | >97 |
KNS2-22-2 | Ac-His-Arg-(pF)DPhe-Tic-NH2 | 13.5 | 20.8 | 676.3 | 677.5 | >95 |
KNS3-10 | Ac-His-Arg-DPhe-Tic-NH2 | 12.8 | 20.1 | 658.3 | 659.5 | >99 |
KNS2-23-4 | Ac-His-Arg-(3,4-diCl)DPhe-Tic-NH2 | 15.6 | 24.2 | 726.3 | 727.4 | >97 |
KNS2-23-7 | Ac-His-Arg-(pMe)DPhe-Tic-NH2 | 14.3 | 22.3 | 672.4 | 673.5 | >97 |
KNS2-23-6 | Ac-His-Arg-(pCF3)DPhe-Tic-NH2 | 15.0 | 23.4 | 726.7 | 727.5 | >98 |
KNS2-23-3 | Ac-His-Arg-(ptBu)DPhe-Tic-NH2 | 17.5 | 26.5 | 714.4 | 715.4 | >95 |
KNS2-23-1 | Ac-His-Arg-DBip-Tic-NH2 | 16.7 | 25.9 | 734.3 | 735.5 | >96 |
KNS2-23-9 | Ac-His-Arg-DTyr-Tic-NH2 | 10.5 | 15.0 | 674.3 | 675.4 | >96 |
KNS2-23-8 | Ac-His-Arg-(pCN)DPhe-Tic-NH2 | 11.5 | 17.2 | 683.3 | 684.3 | >97 |
Peptide | Sequence | mMC1R EC50 (nM) |
---|---|---|
NDP-MSH | Ac-Ser-Tyr-Ser-Nle-Glu-His-DPhe-Arg-Trp-Gly-Lys-Pro-Val-NH2 | 0.009 ± 0.002 |
KNS2-153 | Ac-His-DPhe-Arg-Trp-NH2 | 10 ± 3 |
KNS2-22-4 | Ac-His-Arg-(pI)DPhe-Tic-NH2 | 0.7 ± 0.2 |
KNS2-22-3 | Ac-His-Arg-(pBr)DPhe-Tic-NH2 | 0.7 ± 0.3 |
KNS2-22-1 | Ac-His-Arg-(pCl)DPhe-Tic-NH2 | 0.8 ± 0.2 |
KNS2-22-2 | Ac-His-Arg-(pF)DPhe-Tic-NH2 | 1.8 ± 0.7 |
KNS3-10 | Ac-His-Arg-DPhe-Tic-NH2 | 4.6 ± 0.4 |
KNS2-23-4 | Ac-His-Arg-(3,4-diCl)DPhe-Tic-NH2 | 5 ± 2 |
KNS2-23-7 | Ac-His-Arg-(pMe)DPhe-Tic-NH2 | 1.0 ± 0.3 |
KNS2-23-6 | Ac-His-Arg-(pCF3)DPhe-Tic-NH2 | 5 ± 1 |
KNS2-23-3 | Ac-His-Arg-(ptBu)DPhe-Tic-NH2 | 9 ± 3 |
KNS2-23-1 | Ac-His-Arg-DBip-Tic-NH2 | 0.6 ± 0.1 |
KNS2-23-9 | Ac-His-Arg-DTyr-Tic-NH2 | 40 ± 10 |
KNS-2-23-8 | Ac-His-Arg-(pCN)DPhe-Tic-NH2 | 27 ± 6 |
Peptide | Sequence | mMC3R EC50 (nM) | mMC4R | mMC5R EC50 (nM) | |
---|---|---|---|---|---|
EC50 (nM) | pA2 | ||||
NDP-MSH | Ac-Ser-Tyr-Ser-Nle-Glu-His-DPhe-Arg-Trp-Gly-Lys-Pro-Val-NH2 | 0.52 ± 0.05 | 0.32 ± 0.02 | - | 3.4 ± 0.7 |
KNS2-153 | Ac-His-DPhe-Arg-Trp-NH2 | 190 ± 40 | 12 ± 3 | - | 5 ± 2 |
KNS2-22-4 | Ac-His-Arg-(pI)DPhe-Tic-NH2 | 13 ± 2 | Partial Agonist 150 ± 40 (40% NDP) | 7.3 ± 0.8 | 5 ± 1 |
KNS2-22-3 | Ac-His-Arg-(pBr)DPhe-Tic-NH2 | 90 ± 20 | Partial Agonist 290 ± 50 (55% NDP) | - | 9.7 ± 0.5 |
KNS2-22-1 | Ac-His-Arg-(pCl)DPhe-Tic-NH2 | 120 ± 20 | Partial Agonist 280 ± 60 (70% NDP) | - | 18 ± 6 |
KNS2-22-2 | Ac-His-Arg-(pF)DPhe-Tic-NH2 | 450 ± 70 | Partial Agonist 560 ± 60 (70% NDP) | - | 70 ± 40 |
KNS3-10 | Ac-His-Arg-DPhe-Tic-NH2 | Partial Agonist 900 ± 200 (85% NDP) | 3000 ± 2000 | - | Partial Agonist 200 ± 30 (65% NDP) |
KNS2-23-4 | Ac-His-Arg-(3,4-diCl)DPhe-Tic-NH2 | 400 ± 100 | >100,000 | 6.15 ± 0.05 | 70 ± 7 |
KNS2-23-7 | Ac-His-Arg-(pMe)DPhe-Tic-NH2 | 110 ± 20 | Partial Agonist 700 ± 200 (50% NDP) | - | 17 ± 4 |
KNS2-23-6 | Ac-His-Arg-(pCF3)DPhe-Tic-NH2 | 90 ± 30 | Partial Agonist 600 ± 300 (20% NDP) | 6.5 ± 0.2 | 13 ± 4 |
KNS2-23-3 | Ac-His-Arg-(ptBu)DPhe-Tic-NH2 | Partial Agonist 13 ± 4 (85% NDP) | >100,000 | 6.8 ± 0.3 | 3.4 ± 0.3 |
KNS2-23-1 | Ac-His-Arg-DBip-Tic-NH2 | 14 ± 2 | Partial Agonist 1400 ± 700 (45% NDP) | 5.9 ± 0.2 | 7.6 ± 0.7 |
KNS2-23-9 | Ac-His-Arg-DTyr-Tic-NH2 | Partial Agonist 4200 ± 800 (85% NDP) | >100,000 | <5.5 | 1000 ± 500 |
KNS2-23-8 | Ac-His-Arg-(pCN)DPhe-Tic-NH2 | Partial Agonist 4000 ± 1000 (75% NDP) | 40% @ 100 µM | <5.5 | 500 ± 100 |
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Schlasner, K.N.; Ericson, M.D.; Doering, S.R.; Freeman, K.T.; Weinrich, M.; Haskell-Luevano, C. Structure–Activity Relationships of the Tetrapeptide Ac-His-Arg-(pI)DPhe-Tic-NH2 at the Mouse Melanocortin Receptors: Modification at the (pI)DPhe Position Leads to mMC3R Versus mMC4R Selective Ligands. Molecules 2019, 24, 1463. https://doi.org/10.3390/molecules24081463
Schlasner KN, Ericson MD, Doering SR, Freeman KT, Weinrich M, Haskell-Luevano C. Structure–Activity Relationships of the Tetrapeptide Ac-His-Arg-(pI)DPhe-Tic-NH2 at the Mouse Melanocortin Receptors: Modification at the (pI)DPhe Position Leads to mMC3R Versus mMC4R Selective Ligands. Molecules. 2019; 24(8):1463. https://doi.org/10.3390/molecules24081463
Chicago/Turabian StyleSchlasner, Katherine N., Mark D. Ericson, Skye R. Doering, Katie T. Freeman, Mary Weinrich, and Carrie Haskell-Luevano. 2019. "Structure–Activity Relationships of the Tetrapeptide Ac-His-Arg-(pI)DPhe-Tic-NH2 at the Mouse Melanocortin Receptors: Modification at the (pI)DPhe Position Leads to mMC3R Versus mMC4R Selective Ligands" Molecules 24, no. 8: 1463. https://doi.org/10.3390/molecules24081463