کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
1357814 | 981283 | 2015 | 6 صفحه PDF | دانلود رایگان |
![عکس صفحه اول مقاله: Nitrogenated honokiol derivatives allosterically modulate GABAA receptors and act as strong partial agonists Nitrogenated honokiol derivatives allosterically modulate GABAA receptors and act as strong partial agonists](/preview/png/1357814.png)
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 GABAA 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 α1β2γ2S GABAA receptors. The strongest IGABA enhancement was induced by compound 5 (3-acetamido-4′-ethoxy-3′,5-dipropylbiphenyl-2-ol, Emax: 123.4 ± 9.4% of IGABA-max) and 6 (5′-amino-2-ethoxy-3′,5-dipropylbiphenyl-4′-ol, Emax: 117.7 ± 13.5% of IGABA-max). Compound 5 displayed, however, a significantly higher potency (EC50 = 1.8 ± 1.1 μM) than compound 6 (EC50 = 20.4 ± 4.3 μM).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 μM; 7: EC50 = 33.2 ± 5.1 μM) than the full agonist GABA.
Figure optionsDownload as PowerPoint slide
Journal: Bioorganic & Medicinal Chemistry - Volume 23, Issue 20, 15 October 2015, Pages 6757–6762