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Design,synthesis, and biological activity of new endomorphin analogs with multi-site modifications
Institution:1. La Trobe Institute for Molecular Science, La Trobe University, Victoria 3086, Australia;2. School of Science, University of New South Wales, Canberra 2610, Australia;3. School of Chemistry, University of Wollongong, Wollongong, NSW 2522, Australia;4. Walter and Eliza Hall Institute, Parkville, Victoria 3052, Australia;5. Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3010, Australia;1. Department of Biosciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India;2. Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India;3. Department of Chemistry, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India;4. Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia;5. Organisch-Chemisches Institut, Westfälische Wilhelms-Universität Münster, 48149, Germany;1. Department of Chemistry and Biochemistry, The City College of New York, City University of New York and CUNY Institute for Macromolecular Assemblies, New York, NY 10031, USA;2. Department of Chemistry, Hunter College of CUNY, New York, NY 10065, USA;3. Ph.D. Program in Chemistry, The Graduate Center of the City University of New York (CUNY), New York, NY 10016, USA;4. Ph.D. Program in Biochemistry, The Graduate Center of the City University of New York (CUNY), New York, NY 10016, USA;1. Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, China;2. Key Laboratory of Magnetic Resonance in Biological Systems, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, National Center for Magnetic Resonance in Wuhan, Wuhan Institute of Physics and Mathematics, Chinese Academy of Sciences, Wuhan 430071, China;3. School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China;1. Environmental Health Science Laboratory, Sumitomo Chemical Co., Ltd., 1-98, Kasugadenaka 3-chome, Konohana-ku, Osaka, 554-8558, Japan;2. Faculty of Biomedical Sciences, Graduate School of Medicine, Kobe University, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan;1. Department of Biomolecular Chemistry, Medical University of Lodz, Poland;2. Faculty of Chemistry, University of Wroclaw, Poland
Abstract:Endomorphin (EM)-1 and EM-2 are the most effective endogenous analgesics with efficient separation of analgesia from the risk of adverse effects. Poor metabolic stability and ineffective analgesia after peripheral administration were detrimental for the use of EMs as novel clinical analgesics. Therefore, here, we aimed to establish new EM analogs via introducing different bifunctional d-amino acids at position 2 of (2-furyl)Map4]EMs. The combination of (2-furyl)Map4]EMs with D-Arg2 or D-Cit2 yielded analogs with enhanced binding affinity to the μ-opioid receptor (MOR) and increased stability against enzymatic degradation (t1/2 > 300 min). However, the agonistic activities of these analogs toward MOR were slightly reduced. Similar to morphine, peripheral administration of the analog D-Cit2, (2-furyl)Map4]EM-1 (10) significantly inhibited the pain behavior of mice in multiple pain models. In addition, this EM-1 analog was associated with reduced tolerance, less effect on gastrointestinal mobility, and no significant motor impairment. Compared to natural EMs, the EM analogs synthesized herein had enhanced metabolic stability, bioavailability, and analgesic properties.
Keywords:Adverse effect  Analgesia  Endomorphin  Motor impairment  %MPE"}  {"#name":"keyword"  "$":{"id":"k0035"}  "$$":[{"#name":"text"  "_":"percent maximum possible effect  DOR"}  {"#name":"keyword"  "$":{"id":"k0045"}  "$$":[{"#name":"text"  "$$":[{"#name":"italic"  "_":"δ"}  {"#name":"__text__"  "_":"-opioid receptor  half-maximal effective concentration  half-maximal effective dose  EM"}  {"#name":"keyword"  "$":{"id":"k0075"}  "$$":[{"#name":"text"  "_":"endomorphin  efficacy  iv"}  {"#name":"keyword"  "$":{"id":"k0095"}  "$$":[{"#name":"text"  "_":"intravenous  KOR"}  {"#name":"keyword"  "$":{"id":"k0105"}  "$$":[{"#name":"text"  "_":"κ-opioid receptor  MOR"}  {"#name":"keyword"  "$":{"id":"k0115"}  "$$":[{"#name":"text"  "$$":[{"#name":"italic"  "_":"μ"}  {"#name":"__text__"  "_":"-opioid receptor  PKA"}  {"#name":"keyword"  "$":{"id":"k0125"}  "$$":[{"#name":"text"  "_":"protein kinase A
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