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ACS chemical neuroscience v.8 no.1, 2017년, pp.135 - 146   SCIE
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Discovery of N-Alkyl Catecholamides as Selective Phosphodiesterase-4 Inhibitors with Anti-neuroinflammation Potential Exhibiting Antidepressant-like Effects at Non-emetic Doses

Zhou, Zhong-Zhen (Department of Neuropharmacology and Novel Drug Discovery, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, ); Cheng, Yu-Fang ( Department of Neuropharmacology and Novel Drug Discovery, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, ); Zou, Zheng-Qiang ( Department of Neuropharmacology and Novel Drug Discovery, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, ); Ge, Bing-Chen ( Department of Neuropharmacology and Novel Drug Discovery, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, ); Yu, Hui ( Department of Neuropharmacology and Novel Drug Discovery, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, ); Huang, Cang ( Department of Neuropharmacology and Novel Drug Discovery, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, ); Wang, Hai-Tao ( Department of Neuropharmacology and Novel Drug Discovery, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, ); Yang, Xue-Mei ( Hygien ); Xu, Jiang-Ping ( );
  • 초록  

    Depression involving neuroinflammation is one of the most common disabling and life-threatening psychiatric disorders. Phosphodiesterase 4 (PDE4) inhibitors produce potent antidepressant-like and cognition-enhancing effects. However, their clinical utility is limited by their major side effect of emesis. To obtain more selective PDE4 inhibitors with antidepressant and anti-neuroinflammation potential and less emesis, we designed and synthesized a series of N -alkyl catecholamides by modifying the 4-methoxybenzyl group of our hit compound, FCPE07, with an alkyl side chain. Among these compounds, 10 compounds displayed submicromolar IC 50 values in the mid- to low-nanomolar range. Moreover, 4-difluoromethoxybenzamides 10g and 10j , bearing isopropyl groups, exhibited the highest PDE4 inhibitory activities, with IC 50 values in the low-nanomolar range and with higher selectivities for PDE4 (approximately 5000-fold and 2100-fold over other PDEs, respectively). Furthermore, compound 10j displayed anti-neuroinflammation potential, promising antidepressant-like effects, and a zero incidence rate of emesis at 0.8 mg/kg within 180 min. Graphic Abstract ACS Electronic Supporting Info


  • 주제어

    N-Alkyl catecholamide .   selective phosphodiesterase-4 inhibitors .   anti-neuroinflammation .   antidepressant-like effects .   less side-effect .   structure−activity relationships.  

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