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

Full 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 EC50 near 170 nM. Its potentiating effect was observed only at low (EC10) 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.

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Author information

Author/s: Lynch, Joseph W (JW); Chen, Xuebin (X);

Affiliation: School of Biomedical Sciences and Queensland Brain Institute, University of Queensland, Brisbane, QLD 4072, Australia. j.lynch(-atsign-)uq.edu.au

Journal and publication information

Publication Type: Journal Article; Research Support, Non-U.S. Gov't

Journal: Neuroscience letters (Neurosci Lett), published in Ireland. (Language: eng)

Reference: 2008-Apr; vol 435 (issue 2) : pp 147-51

Dates: Created 2008/04/02; Completed 2008/07/30;

PMID: 18329806, status: MEDLINE (last retrieval date: 11/6/2008)

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

Bilobalides - chemistry; pharmacology
Cell Line, Transformed
Dose-Response Relationship, Drug
Dose-Response Relationship, Radiation
Electric Stimulation - methods
GABA Antagonists - pharmacology
Ginkgo biloba - chemistry
Glycine - pharmacology
Humans

Humans
Membrane Potentials - drug effects; physiology; radiation effects
Mutation - physiology
Patch-Clamp Techniques
Picrotoxin - pharmacology
Protein Subunits - genetics; metabolism
Pyrans - pharmacology
Receptors, Glycine - agonists; genetics
Transfection - methods

Associated Chemicals: 4-hydroxy-4-tert-butyl-2,3,5,6-tetrahydrothiopyran-1-oxide (0) ; Bilobalides (0) ; GABA Antagonists (0) ; Protein Subunits (0) ; Pyrans (0) ; Receptors, Glycine (0) ; Picrotoxin (124-87-8) ; Glycine (56-40-6)

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