Data_Sheet_1_Cyclizing Painkillers: Development of Backbone-Cyclic TAPS Analogs.PDF
Painkillers are commonly used medications. Native peptide painkillers suffer from various pharmacological disadvantages, while small molecule painkillers like morphine are highly addictive. We present a general approach aimed to use backbone-cyclization to develop a peptidomimetic painkiller. Backbone-cyclization was applied to transform the linear peptide Tyr-Arg-Phe-Sar (TAPS) into an active backbone-cyclic peptide with improved drug properties. We designed and synthesized a focused backbone-cyclic TAPS library with conformational diversity, in which the members of the library have the generic name TAPS c(n-m) where n and m represent the lengths of the alkyl chains on the nitrogens of Gly and Arg, respectively. We used a combined screening approach to evaluate the pharmacological properties and the potency of the TAPS c(n-m) library. We focused on an in vivo active compound, TAPS c(2-6), which is metabolically stable and has the potential to become a peripheral painkiller being a full μ opioid receptor functional agonist. To prepare a large quantity of TAPS c(2-6), we optimized the conditions of the on-resin reductive alkylation step to increase the efficiency of its SPPS. NMR was used to determine the solution conformation of the peptide lead TAPS c(2-6).
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References
- https://doi.org//10.1016/j.bmcl.2017.03.016
- https://doi.org//10.1021/acs.oprd.8b00159
- https://doi.org//10.1021/acschemneuro.8b00085
- https://doi.org//10.1021/ja303200d
- https://doi.org//10.2174/0929867324666170216095233
- https://doi.org//10.1002/anie.200705797
- https://doi.org//10.1016/j.peptides.2019.170223
- https://doi.org//10.1111/j.1476-5381.1981.tb16797.x
- https://doi.org//10.1016/S0960-894X(00)00562-X
- https://doi.org//10.1021/jm011059z
- https://doi.org//10.1146/annurev-neuro-080317-061522
- https://doi.org//10.1007/BF02443482
- https://doi.org//10.1074/jbc.273.30.18848
- https://doi.org//10.1016/0736-5748(92)90003-I
- https://doi.org//10.1038/s41467-018-06576-5
- https://doi.org//10.1016/j.peptides.2003.09.020
- https://doi.org//10.1034/j.1399-3011.2001.00936.x
- https://doi.org//10.1046/j.1397-002x.2000.0780.x
- https://doi.org//10.2174/1568026043451663
- https://doi.org//10.1016/j.peptides.2018.12.002
- https://doi.org//10.1111/j.1471-4159.1981.tb06336.x
- https://doi.org//10.1039/C9OB00882A
- https://doi.org//10.1016/j.bmc.2010.09.046
- https://doi.org//10.1016/j.bmc.2012.03.039
- https://doi.org//10.1016/0168-3659(94)90072-8
- https://doi.org//10.1038/nature14886
- https://doi.org//10.3987/COM-07-S(U)40
- https://doi.org//10.1016/j.bmc.2013.03.019
- https://doi.org//10.1016/j.bmc.2010.04.053
- https://doi.org//10.1002/med.21639
- https://doi.org//10.1002/cmdc.201700103
- https://doi.org//10.1021/acs.jmedchem.5b01899
- https://doi.org//10.3389/fphar.2018.01388
- https://doi.org//10.1016/j.biopsych.2019.08.028
- https://doi.org//10.1002/chem.201403839
- https://doi.org//10.1021/acs.chemrev.6b00838
- https://doi.org//10.1002/anie.201412070
- https://doi.org//10.1016/j.ejmech.2015.12.012
- https://doi.org//10.1111/bph.13750
- https://doi.org//10.2174/0929867323666160427123005
- https://doi.org//10.2147/JPR.S190160
- https://doi.org//10.1007/164_2016_17
- https://doi.org//10.2174/1568026618666180518092333
- https://doi.org//10.2174/1568026618666180518094322
- https://doi.org//10.1016/0143-4179(85)90036-8
- https://doi.org//10.1248/cpb.33.1528
- https://doi.org//10.1016/0006-291X(84)91435-9
- https://doi.org//10.3389/fchem.2020.00447
- https://doi.org//10.1007/s00726-018-2585-8
- https://doi.org//10.1021/acsmedchemlett.7b00044
- https://doi.org//10.1016/S1471-4892(01)00005-4
- https://doi.org//10.1248/cpb.33.4865
- https://doi.org//10.1021/jm2003969
- https://doi.org//10.1093/brain/awg115
- https://doi.org//10.1016/j.chembiol.2015.05.012
- https://doi.org//10.1002/pep2.24078
- https://doi.org//10.1021/mp500046f
- https://doi.org//10.3389/fpsyt.2019.00157
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Categories
- Geochemistry
- Biochemistry
- Organic Chemistry
- Medical Biochemistry: Proteins and Peptides (incl. Medical Proteomics)
- Nuclear Chemistry
- Medical Biochemistry and Metabolomics not elsewhere classified
- Analytical Biochemistry
- Cell Neurochemistry
- Physical Organic Chemistry
- Enzymes
- Organic Green Chemistry
- Environmental Chemistry (incl. Atmospheric Chemistry)
- Catalysis and Mechanisms of Reactions
- Electroanalytical Chemistry
- Analytical Chemistry not elsewhere classified
- Environmental Chemistry
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- Inorganic Chemistry