Sarcophine and (7S, 8R)-dihydroxydeepoxysarcophine from the Red Sea soft coral Sarcophyton glaucum as in vitro and in vivo modulators of glycine receptors.

Autor: Saleh HA; Department of Pharmaceutical Chemistry, German University in Cairo, New Cairo, Egypt., Raafat KM; Department of Biochemistry, German University in Cairo, New Cairo, Egypt., Temraz TA; Department of Marine Sciences, Suez Canal University, Ismailia, Egypt., Noureldin N; Department of Pharmaceutical Chemistry, German University in Cairo, New Cairo, Egypt. Electronic address: nazih.noureldin@guc.edu.eg., Breitinger HG; Department of Biochemistry, German University in Cairo, New Cairo, Egypt. Electronic address: hans.breitinger@guc.edu.eg., Breitinger U; Department of Biochemistry, German University in Cairo, New Cairo, Egypt.
Jazyk: angličtina
Zdroj: Neurotoxicology [Neurotoxicology] 2020 Sep; Vol. 80, pp. 105-111. Date of Electronic Publication: 2020 Jul 20.
DOI: 10.1016/j.neuro.2020.07.002
Abstrakt: 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 LD 50 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 K I values 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.
(Copyright © 2020 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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