Structural analogues of the natural products magnolol and honokiol as potent allosteric potentiators of GABAA receptors |
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| Institution: | 1. State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, The Chinese Academy of Sciences, Fuzhou, Fujian 350002, PR China;2. College of Materials Science and Engineering, Fujian Normal University, Fuzhou, Fujian 350007, PR China;1. State Key Laboratory of Marine Resource Utilization in South China Sea, Hainan University, 58 Renmin Rd, Haikou 570228, China;2. Key Laboratory of Tropical Biological Resources for Ministry of Education, Hainan University, 58 Renmin Rd, Haikou 570228, China;3. Hainan Provincial Key Laboratory for Tropical Hydrobiology and Biotechnology, College of Marine Science, Hainan University, 58 Renmin Rd, Haikou 570228, China |
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| Abstract: | Biphenylic compounds related to the natural products magnolol and 4′-O-methylhonokiol were synthesized, evaluated and optimized as positive allosteric modulators (PAMs) of GABAA receptors. The most efficacious compounds were the magnolol analog 5-ethyl-5′-hexylbiphenyl-2,2′-diol (45) and the honokiol analogs 4′-methoxy-5-propylbiphenyl-2-ol (61), 5-butyl-4′-methoxybiphenyl-2-ol (62) and 5-hexyl-4′-methoxybiphenyl-2-ol (64), which showed a most powerful potentiation of GABA-induced currents (up to 20-fold at a GABA concentration of 3 μM). They were found not to interfere with the allosteric sites occupied by known allosteric modulators, such as benzodiazepines and N-arachidonoylglycerol. These new PAMs will be useful as pharmacological tools and may have therapeutic potential for mono-therapy, or in combination, for example, with GABAA receptor agonists. |
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| Keywords: | Allosteric modulation Honokiol Ion channel Magnolol Medicinal plant Natural product Positive allosteric modulator (PAM) Synthesis |
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