Nitrogenated honokiol derivatives allosterically modulate GABA(A) receptors and act as strong partial agonists

作者：Bernaskova Marketa; Schoeffmann Angela; Schuehly Wolfgang^*; Hufner Antje; Baburin Igor; Hering Steffen

来源：Bioorganic & Medicinal Chemistry, 2015, 23(20): 6757-6762.

DOI：10.1016/j.bmc.2015.08.034

• Honokiol derivatives
• GABA(A) receptor
• Nitrogenation
• Magnolia

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 alpha(1)beta(2)gamma(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 IGABA-max) and 6 (5'-amino-2-ethoxy-3',5-dipropylbiphenyl-4'-ol, E-max: 117.7 +/- 13.5% of IGABA-max). Compound 5 displayed, however, a significantly higher potency (EC50 = 1.8 +/- 1.1 mu M) than compound 6 (EC50 = 20.4 +/- 4.3 mu 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 IGABA-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 mu M; 7: EC50 = 33.2 +/- 5.1 mu M) than the full agonist GABA.

• 出版日期2015-10-15