Characterization of a new synthetic isoflavonoid with inverse agonist activity at the central benzodiazepine receptor

European Journal of Pharmacology
D V S LopesF Noël

Abstract

Research aimed at developing selective drugs acting on gamma-aminobutyric acid (GABA)A receptors introduced compounds from diverse chemical classes unrelated to the 1,4-benzodiazepines, including flavonoids. These studies also revealed the potential use of inverse agonists as cognition-enhancing agents. Here we report pharmacological properties of the novel synthetic isoflavonoid 2-methoxy-3,8,9-trihydroxy coumestan (PCALC36). PCALC36 displaced [3H]flunitrazepam binding to rat brain synaptosomes with an IC50 of 13.8 microM. Scatchard analysis of the effect of PCALC36 showed a concentration-dependent reduction of the Bmax of [3H]flunitrazepam, without a marked change in Kd. This effect could be reversed by diluting and washing the preparation. Addition of 20-microM GABA shifted to the right the inhibition curve of PCALC36 on [3H]flunitrazepam binding (IC50 ratio of 0.68), which is characteristic for inverse agonists. PCALC36 produced little change in the GABAergic tonic currents recorded by whole-cell patch clamp in cultured rat hippocampal neurones, but it caused a 20% reduction in miniature inhibitory postsynaptic current amplitude and completely antagonised the full (direct) agonist midazolam in a quickly reversible manner. T...Continue Reading

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Citations

Sep 28, 2015·Restorative Neurology and Neuroscience·Javier GálvezEduardo Calixto
Jan 28, 2006·Pharmacology, Biochemistry, and Behavior·Jeanne M FaheyDavid J Greenblatt
Apr 21, 2009·European Journal of Pharmacology·Jean Pierre Barros ThibautFrançois Noël
Oct 30, 2016·Journal of Natural Products·Jianfei ShengYong Zou
Nov 23, 2017·Frontiers in Pharmacology·Vinicius F CarvalhoMarco A Martins
Jul 14, 2006·The Journal of Pharmacology and Experimental Therapeutics·Hélio R SantosNewton G Castro

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