Novel Plant Substances Acting as β Subunit Isoform-Selective Positive Allosteric Modulators of GABAA Receptors

• Published in: Molecular pharmacology 2005-09, Vol.68 (3), p.787
• Main Authors: Roland Baur, Urs Simmen, Martin Senn, Urs Séquin, Erwin Sigel
• Format: Article
• Language: English
• ISSN: 0026-895X; 1521-0111
• DOI: 10.1124/mol.105.011882

GABA A receptors are modulated by a large variety of compounds. A common chemical characteristic of most of these modulators is that they contain a cyclic entity. Three linear molecules of a polyacetylene structure were isolated from the East African medicinal plant Cussonia zimmermannii Harms and shown to allosterically stimulate GABA A receptors. Stimulation was not abolished by the absence of the γ 2 subunit, the benzodiazepine antagonist Ro15-1788 (8-fluoro-5,6-dihydro-5-methyl-6-oxo-4 H -imidazo[1,5- a ][1,4]benzodiazepine-3-carboxylic acid ethyl ester), or the point mutation β 2 N265S that abolishes effects by loreclezole. At a concentration of 30 μM, the substances by themselves elicited only tiny currents. Maximal stimulation at α 1 β 2 γ 2 amounted to 110 to 450% for the three substances, and half-maximal stimulation was observed at concentrations of 1 to 2 μM. Stimulation was subunit composition-dependent and was for the substance MS-1, α 1 β 2 γ 2 ≈ α 1 β 2 ≈ α 3 β 2 γ 2 > α 2 β 2 γ 2 > α 5 β 2 γ 2 ≈ α 1 β 3 γ 2 ≈ α 6 β 2 γ 2 > α 1 β 1 γ 2 , for MS-2 α 1 β 2 γ 2 ≈ α 3 β 2 γ 2 ≈ α 1 β 2 > α 2 β 2 γ 2 ≈ α 6 β 2 γ 2 ≈ α 5 β 2 γ 2 > α 1 β 1 γ 2 , and for MS-4, α 1 β 2 γ 2 ≈ α 1 β 2 ≈ α 5 β 2 γ 2 ≈ α 3 β 2 γ 2 ≈ α 2 β 2 γ 2 > α 6 β 2 γ 2 ≫ α 1 β 1 γ 2 . Maximal stimulation by MS-1 was 450% at α 1 β 2 γ 2 , 80% at α 1 β 1 γ 2 , and 150% at α 1 β 3 γ 2 . MS-1 was thus specific for receptors containing the β 2 subunit. The reversal potential was unaffected by 10 μM MS-1, whereas apparent picrotoxin affinity for current inhibition was increased approximately 3-fold. In summary, these positive allosteric modulators of GABA A receptors of plant origin have a novel unusual chemical structure and act at a site independent of that of benzodiazepines and loreclezole.