Subunit-specitic potentiation of recombinant glycine receptors by NV-31, a bilobalide-derived compound

Lynch, Joseph W. and Chen, Xuebin (2008) Subunit-specitic potentiation of recombinant glycine receptors by NV-31, a bilobalide-derived compound. Neuroscience letters, 435 2: 147-151. doi:10.1016/j.neulet.2008.02.022

Author Lynch, Joseph W.
Chen, Xuebin
Title Subunit-specitic potentiation of recombinant glycine receptors by NV-31, a bilobalide-derived compound
Journal name Neuroscience letters   Check publisher's open access policy
ISSN 0304-3940
Publication date 2008-04
Year available 2008
Sub-type Article (original research)
DOI 10.1016/j.neulet.2008.02.022
Volume 435
Issue 2
Start page 147
End page 151
Total pages 5
Place of publication East Park Shannon, CO, Ireland
Publisher Elsevier Ireland
Collection year 2009
Language eng
Subject C1
110903 Central Nervous System
920111 Nervous System and Disorders
Abstract Bilobalide, a major bioactive component of Ginkgo biloba herbal extracts, exhibits neuroprotective and anti-ischaemic activity. However, its therapeutic potential is limited because of its instability. Attempts to synthesise a more stable analogue culminated in the development of NV-31. This compound recapitulates some aspects of bilobalide pharmacology. However, although bilobalide inhibits recombinant glycine receptor Cl channels (GlyRs), NV-31 potentiates hippocampal neuron GlyRs. Because of the possible therapeutic relevance of this effect, the present study investigated the molecular mechanism and subunit specificity of NV-31 actions at recombinantly expressed alpha1, alpha1beta, alpha2 and alpha3 GlyRs. NV-31 potentiated alpha1 GlyRs by approximately 135 % with an EC(50) near 170nM. Its potentiating effect was observed only at low (EC(10)) glycine concentrations. The magnitude of its potentiating effect was reduced at alpha1beta GlyRs and it had no effect at all at alpha2 and alpha3 GlyRs. NV-31 was unlikely to bind at the bilobalide pore-binding site as its efficacy was not affected by the alpha1 subunit G2'A and T6'S mutations. However, the S15'C mutation to the alcohol-binding site abolished its effects, suggesting that NV-31 modulates the GlyR via a specific (steric or allosteric) interaction with S15'. GlyRs are potential therapeutic targets for chronic anti-inflammatory pain and movement disorders. NV-31, as a positive modulator of these receptors, thus remains viable as a therapeutic candidate for these disorders.
Keyword Chloride channel
Inhibitory neurotransmission
Ginkgo biloba
Molecular pharmacology
Q-Index Code C1
Q-Index Status Confirmed Code
Additional Notes Available online 16 February 2008.

Document type: Journal Article
Sub-type: Article (original research)
Collections: 2009 Higher Education Research Data Collection
Queensland Brain Institute Publications
School of Biomedical Sciences Publications
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Citation counts: TR Web of Science Citation Count  Cited 6 times in Thomson Reuters Web of Science Article | Citations
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Created: Wed, 19 Mar 2008, 09:49:39 EST