Hydroxylated biphenyl derivatives are positive modulators of human GABA_A receptors

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• 作者：Maria Paola Mascia ; Davide Fabbri ; Maria Antonietta Dettori ; Giovanni Ledda ; Giovanna Delogu ; Giovanni Biggio
• 关键词：GABAA receptors ; Xenopus oocytes ; Hydroxylated biphenyl derivatives
• 刊名：European Journal of Pharmacology
• 出版年：2012
• 出版时间：15 October, 2012
• 年：2012
• 卷：693
• 期：1-3
• 页码：45-50
• 全文大小：343 K

文摘

A series of 7 hydroxylated biphenyl derivatives (1-7) were prepared to evaluate their ability to modulate the function of several ligand gated ion channel (LGIC) recombinant receptors expressed in Xenopus laevis oocytes. Compounds 1, 3, 4, 6 and 7 are natural occurring compounds whereas the synthesis of compounds 2 and 5 was previously reported (). None of the compounds tested were able to modify, the activity of the strychnine-sensitive glycine receptor, or the activity of nicotinic receptor. The function of the 5HT_3A receptor was partially inhibited by all compounds tested, however this inhibition occurred at relatively high concentrations (100 ¦ÌM). All compounds, with the exception of compound 6, potentiate the action of gamma-aminobutyric acid (GABA)-evoked Cl^? currents in Xenopus laevis oocytes expressing recombinant human ¦Á₁¦Â₂¦Ã_2L GABA_A receptors. Compounds 1, 2, 5 and 7 enhance the function of the GABA_A receptor at concentrations higher than 3-10 ¦ÌM. Compound 4 was the most efficacious. However, compound 3 was the most potent (EC₅₀ 0.8 ¦ÌM). The potency of compound 3 in modulating the function of the GABA_A receptor was comparable to that of diazepam, propofol or allopregnanolone. The enhancement of the GABA evoked Cl^? currents by compound 3 was not affected by flumazenil. Compound 3 did not induce loss of the righting reflex in rats suggesting that it is not an anesthetic agent, however, its ability in protecting the animals from seizures induced by picrotoxin confirm that its action occurs through the GABA_A receptor.