Sarcophine and (7S, 8R)-dihydroxydeepoxysarcophine from the Red Sea soft coral Sarcophyton glaucum as in vitro and in vivo modulators of glycine receptors |
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| Affiliation: | 1. Department of Pharmaceutical Chemistry, German University in Cairo, New Cairo, Egypt;2. Department of Biochemistry, German University in Cairo, New Cairo, Egypt;3. Department of Marine Sciences, Suez Canal University, Ismailia, Egypt;1. State Key Laboratory of Natural and Biomimetic Drugs, Institute of Ocean Research, Peking University, Beijing 100191, PR China;2. State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100190, PR China;3. Guangxi University of Chinese Medicine, Nanning 530001, PR China;4. National Museum of Natural History Naturalis, 2300 RA Leiden, The Netherlands;1. School of Biological Science and Technology, University of Jinan, 336 West Road of Nan Xinzhuang, Jinan 250022, China;2. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Zhangjiang Hi-Tech Park, Shanghai 201203, China;3. University of Chinese Academy of Sciences, 19A Yuquan Road, Beijing 100049, China;4. Open Studio for Druggability Research of Marine Lead Compounds, Qingdao National Laboratory for Marine Science and Technology, Wenhai Road, Aoshanwei, Jimo, Qingdao 266237, China;1. State Key Laboratory of Natural and Biomimetic Drugs, Peking University, 100191 Beijing, PR China;2. National Museum of Natural History Naturalis, 2300 RA Leiden, The Netherlands;3. Institute of Pharmaceutical Biology and Biotechnology, Heinrich-Heine University, 40225 Duesseldorf, Germany;1. Institute of Marine Biochemistry (IMBC), Vietnam Academy of Science and Technology (VAST), 18 Hoang Quoc Viet, Caugiay, Hanoi, Viet Nam;2. College of Pharmacy, Chungnam National University, Daejeon 305-64, Republic of Korea;3. Gyeongbuk Institute for Bio-Industry (GIB), Andong-City, Gyeongbuk 760-380, Republic of Korea |
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| Abstract: | The inhibitory glycine receptor (GlyR) is a key mediator of synaptic signalling in spinal cord, brain stem, and higher centres of the central nervous system. We examined the glycinergic activity of sarcophine (SN), a marine terpenoid known for its various biological activities, and its trans-diol derivative (7S, 8R)-dihydroxy-deepoxysarcophine (DSN). SN was isolated from the Red Sea soft coral Sacrophyton glaucum, DSN was semisynthesized by hydrolysis of the epoxide ring. In cytotoxicity tests against HEK293 cells, SN and DSN had LD50 values of 29.3 ± 3.0 mM and 123.5 ± 13.0 mM, respectively. Both compounds were tested against recombinant human α1 glycine receptors in HEK293 cells using whole-cell recording techniques. Both, SN and DSN were shown for the first time to be inhibitors of recombinant glycine receptors, with KIvalues of 2.1 ± 0.3 μM for SN, and 109 ± 9 μM for DSN. Receptor inhibition was also studied in vivo in a mouse model of strychnine toxicity. Surprisingly, in mouse experiments strychnine inhibition was not augmented by either terpenoid. While DSN had no significant effect on strychnine toxicity, SN even delayed strychnine effects. This could be accounted for by assuming that strychnine and sarcophine derivatives compete for the same binding site on the receptor, so the less toxic sarcophine can prevent strychnine from binding. The combination of modulatory activity and low level of toxicity makes sarcophines attractive structures for novel glycinergic drugs. |
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| Keywords: | Glycine receptor Ion channels Inhibition Sarcophine (7S8R)-dihydroxydeepoxysarcophine Marine organisms |
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