Discovery of N-Alkyl Catecholamides as Selective Phosphodiesterase-4 Inhibitors with Anti-neuroinflammation Potential Exhibiting Antidepressant-like Effects at Non-emetic Doses.
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 IC50values in the mid- to low-nanomolar range. Moreover, 4-difluoromethoxybenzamides 10g and 10j, bearing isopropyl groups, exhibited the highest PDE4 inhibitory activities, with IC50values 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.
Department of Neuropharmacology and Novel Drug Discovery, School of Pharmaceutical Sciences, Southern Medical University , Guangzhou 510515, China.
Zhong-Zhen
ZZ
Zhou
Department of Neuropharmacology and Novel Drug Discovery, School of Pharmaceutical Sciences, Southern Medical University , Guangzhou 510515, China.
Yu-Fang
YF
Cheng
Department of Neuropharmacology and Novel Drug Discovery, School of Pharmaceutical Sciences, Southern Medical University , Guangzhou 510515, China.
Zheng-Qiang
ZQ
Zou
Department of Neuropharmacology and Novel Drug Discovery, School of Pharmaceutical Sciences, Southern Medical University , Guangzhou 510515, China.
Bing-Chen
BC
Ge
Department of Neuropharmacology and Novel Drug Discovery, School of Pharmaceutical Sciences, Southern Medical University , Guangzhou 510515, China.
Hui
H
Yu
Department of Neuropharmacology and Novel Drug Discovery, School of Pharmaceutical Sciences, Southern Medical University , Guangzhou 510515, China.
Cang
C
Huang
Department of Neuropharmacology and Novel Drug Discovery, School of Pharmaceutical Sciences, Southern Medical University , Guangzhou 510515, China.
Hai-Tao
HT
Wang
Hygiene Detection Center, School of Public Health, Southern Medical University , Guangzhou 510515, China.
Xue-Mei
XM
Yang
Department of Neuropharmacology and Novel Drug Discovery, School of Pharmaceutical Sciences, Southern Medical University , Guangzhou 510515, China.
Jiang-Ping
JP
Xu
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000928:Antidepressive Agents / Q000737:chemistry / Q000627:therapeutic use*; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D003863:Depression / Q000188:drug therapy*; D004195:Disease Models, Animal; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004660:Encephalitis / Q000139:chemically induced / Q000188:drug therapy*; D005106:Exploratory Behavior / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D019417:Hindlimb Suspension / Q000379:methods / Q000523:psychology; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D062105:Molecular Docking Simulation; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D058988:Phosphodiesterase 4 Inhibitors / Q000737:chemistry* / Q000627:therapeutic use*; D020889:Rolipram / Q000494:pharmacology / Q000627:therapeutic use; D013550:Swimming / Q000523:psychology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014839:Vomiting / Q000188:drug therapy / Q000662:veterinary
D000893:Anti-Inflammatory Agents; D000928:Antidepressive Agents; D008070:Lipopolysaccharides; D058988:Phosphodiesterase 4 Inhibitors; D014409:Tumor Necrosis Factor-alpha; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D020889:Rolipram
N-Alkyl catecholamide; anti-neuroinflammation; antidepressant-like effects; less side-effect; selective phosphodiesterase-4 inhibitors; structure−activity relationships