TY - JOUR T1 - Novel Plant Substances Acting as β Subunit Isoform-Selective Positive Allosteric Modulators of GABA<sub>A</sub> Receptors JF - Molecular Pharmacology JO - Mol Pharmacol SP - 787 LP - 792 DO - 10.1124/mol.105.011882 VL - 68 IS - 3 AU - Roland Baur AU - Urs Simmen AU - Martin Senn AU - Urs Séquin AU - Erwin Sigel Y1 - 2005/09/01 UR - http://molpharm.aspetjournals.org/content/68/3/787.abstract N2 - GABAA 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 GABAA receptors. Stimulation was not abolished by the absence of the γ2 subunit, the benzodiazepine antagonist Ro15-1788 (8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid ethyl ester), or the point mutation β2N265S that abolishes effects by loreclezole. At a concentration of 30 μM, the substances by themselves elicited only tiny currents. Maximal stimulation at α1β2γ2 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, α1β2γ2 ≈ α1β2 ≈ α3β2γ2 &gt; α2β2γ2 &gt; α5β2γ2 ≈ α1β3γ2 ≈ α6β2γ2 &gt; α1β1γ2, for MS-2 α1β2γ2 ≈ α3β2γ2 ≈ α1β2 &gt; α2β2γ2 ≈ α6β2γ2 ≈ α5β2γ2 &gt; α1β1γ2, and for MS-4, α1β2γ2 ≈ α1β2 ≈ α5β2γ2 ≈ α3β2γ2 ≈ α2β2γ2 &gt; α6β2γ2 ≫ α1β1γ2. Maximal stimulation by MS-1 was 450% at α1β2γ2, 80% at α1β1γ2, and 150% at α1β3γ2. MS-1 was thus specific for receptors containing the β2 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 GABAA receptors of plant origin have a novel unusual chemical structure and act at a site independent of that of benzodiazepines and loreclezole. ER -