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

Department of Pharmacology, University of Bern, Bern, Switzerland (R.B., E.S.); and Departments of Pharmacy (U.Si.) and Chemistry (M.S., U.Sé.), University of Basel, Basel, Switzerland

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 ₂ 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 ₂N265S that abolishes effects by loreclezole. At a concentration of 30 µM, the substances by themselves elicited only tiny currents. Maximal stimulation at ₁₂₂ 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, _{122 12 322} > ₂₂₂ > _{522 132 622} > ₁₁₂, for MS-2 _{122 322 12} > _{222 622 522} > ₁₁₂, and for MS-4, _{122 12 522 322 222} > ₆₂₂ >> ₁₁₂. Maximal stimulation by MS-1 was 450% at ₁₂₂, 80% at ₁₁₂, and 150% at ₁₃₂. MS-1 was thus specific for receptors containing the 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.

Address correspondence to: Dr. Erwin Sigel, Department of Pharmacology, Friedbuehlstrasse 49, CH-3010 Bern, Switzerland. E-mail: erwin.sigel{at}pki.unibe.ch