Nitrogenated honokiol derivatives allosterically modulate GABA_A receptors and act as strong partial agonists

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• 作者：Marketa Bernaskova^a ; Angela Schoeffmann^d ; Wolfgang Schuehly^b ; ^c ; ^{wolfgang.schuehly@uni-graz.at" class="auth_mail" title="E-mail the corresponding author} ; Antje Hufner^a ; Igor Baburin^d ; Steffen Hering^d
• 关键词：Honokiol derivatives ; GABAA receptor ; Nitrogenation ; Magnolia
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2015
• 出版时间：15 October 2015
• 年：2015
• 卷：23
• 期：20
• 页码：6757-6762
• 全文大小：767 K

文摘

In traditional Asian medicinal systems, preparations of the root and stem bark of Magnolia species are widely used to treat anxiety and other nervous disturbances. The biphenyl-type neolignan honokiol together with its isomer magnolol are the main constituents of Magnolia bark extracts. We have previously identified a nitrogen-containing honokiol derivative (3-acetylamino-4′-O-methylhonokiol, AMH) as a high efficient modulator of GABA_A receptors. Here we further elucidate the structure-activity relation of a series of nitrogenated biphenyl-neolignan derivatives by analysing allosteric modulation and agonistic effects on 伪₁尾₂纬_2S GABA_A receptors. The strongest I_GABA enhancement was induced by compound 5 (3-acetamido-4′-ethoxy-3′,5-dipropylbiphenyl-2-ol, E_max: 123.4 ± 9.4% of I_GABA-max) and 6 (5′-amino-2-ethoxy-3′,5-dipropylbiphenyl-4′-ol, E_max: 117.7 ± 13.5% of I_GABA-max). Compound 5 displayed, however, a significantly higher potency (EC₅₀ = 1.8 ± 1.1 渭M) than compound 6 (EC₅₀ = 20.4 ± 4.3 渭M).

Honokiol, AMH and four of the derivatives induced significant inward currents in the absence of GABA. Strong partial agonists were honokiol (inducing 78 ± 6% of I_GABA-max), AMH (63 ± 6%), 5′-amino-2-O-methylhonokiol (1) (59 ± 1%) and 2-methoxy-5′-nitro-3′,5-dipropylbiphenyl-4′-ol (3) (52 ± 1%). 3-N-Acetylamino-4′-ethoxy-3′,5-dipropyl-biphenyl-4′-ol (5) and 3-amino-4′-ethoxy-3′,5-dipropyl-biphenyl-4′-ol (7) were less efficacious but even more potent (5: EC₅₀ = 6.9 ± 1.0 渭M; 7: EC₅₀ = 33.2 ± 5.1 渭M) than the full agonist GABA.