Background
Phenamil is a selective inhibitor of transient receptor potentials (TRPs) and acid-sensing ion channels (ASICs) [1]. Phenamil is an amiloride analogs and a more potent and less reversible epithelial sodium channel (ENaC) blocker with an IC50 of 400 nM [2]. Phenamil inhibited TRPP3 -mediated Ca2+ transport with an IC50 of 140 nM in a Ca2+ uptake assay [3].
Phenamil (10 μM) Treatment of M2-10B4 (M2) mouse (mesenchymal stem cells) MSCs for 6 days with 10 μM phenamil markedly stimulated expression of the genes encoding ALP, Runx2, OCN, and osterix. Phenamil induces osteogenic gene expression and mineralization in both MSC and primary calvariae organ cultures [4]. Phenamil (10 μM) induced the expression of PPARγ within 24 h in 3T3-F442A preadipocyte cell lines. Phenamil act as a new proadipogenic compound [5].
Phenamil (15 or 30 mg/kg; 21 days) reduced chronic-hypoxia-induced pulmonary artery hypertension (PAH). Infusion of phenamil during hypoxia treatment inhibited pulmonary vascular remodeling [6].
参考文献:
[1]. Chan M C, Weisman A S, Kang H, et al. The amiloride derivative phenamil attenuates pulmonary vascular remodeling by activating NFAT and the bone morphogenetic protein signaling pathway[J]. Molecular and cellular biology, 2011, 31(3): 517-530.
[2]. Hirsh A J, Molino B F, Zhang J, et al. Design, synthesis, and structure? activity relationships of novel 2-substituted pyrazinoylguanidine epithelial sodium channel blockers: drugs for cystic fibrosis and chronic bronchitis[J]. Journal of medicinal chemistry, 2006, 49(14): 4098-4115.
[3]. Dai X Q, Ramji A, Liu Y, et al. Inhibition of TRPP3 channel by amiloride and analogs[J]. Molecular pharmacology, 2007, 72(6): 1576-1585.
[4]. Park K W, Waki H, Kim W K, et al. The small molecule phenamil induces osteoblast differentiation and mineralization[J]. Molecular and cellular biology, 2009, 29(14): 3905-3914.
[5]. Park K W, Waki H, Choi S P, et al. The small molecule phenamil is a modulator of adipocyte differentiation and PPARγ expression [S][J]. Journal of lipid research, 2010, 51(9): 2775-2784.
[6]. Chan M C, Weisman A S, Kang H, et al. The amiloride derivative phenamil attenuates pulmonary vascular remodeling by activating NFAT and the bone morphogenetic protein signaling pathway[J]. Molecular and cellular biology, 2011, 31(3): 517-530.
Phenamil 是瞬时受体电位 (TRP) 和酸敏感离子通道 (ASIC) 的选择性抑制剂[1]。 Phenamil 是一种阿米洛利类似物，是一种更有效且可逆性更差的上皮钠通道 (ENaC) 阻断剂，IC50 为 400 nM [2]。在 Ca2+ 摄取试验中，Phenamil 抑制 TRPP3 介导的 Ca2+ 转运，IC50 为 140 nM [3]。
Phenamil (10 μM) 用 10 μM phenamil 处理 M2-10B4 (M2) 小鼠（间充质干细胞）MSCs 6 天，可显着刺激编码 ALP、Runx2、OCN 和 osterix 的基因的表达。 Phenamil 在 MSC 和原代颅骨器官培养物中诱导成骨基因表达和矿化[4]。 Phenamil (10 μM) 在 24 小时内诱导 3T3-F442A 前脂肪细胞系中 PPARγ 的表达。 Phenamil 作为一种新的促脂肪形成化合物[5]。
Phenamil（15 或 30 mg/kg；21 天）可减少慢性缺氧引起的肺动脉高压 (PAH)。缺氧治疗期间输注非那米抑制肺血管重构[6]。
Protocol
| Cell experiment [1]: |
|
Cell lines
|
Osteoblast-like MC3T3-E1 cells
|
|
Preparation Method
|
The cells were maintained in regular growth medium, i.e. α-minimal essential medium supplemented with 10% fetal bovine serum (FBS), 100 U/ml penicillin G and 100 mg/ml streptomycin. The culture medium, with or without 10 μM phenamil, was replaced every 3-4 days.
|
|
Reaction Conditions
|
10 μM for 14 days
|
|
Applications
|
Phenamil-treated and -untreated control cells showed a statistically significant increase in cell proliferation from day 7 to day 14.
|
| Animal experiment [2]: |
|
Animal models
|
Male Sprague-Dawley rats
|
|
Preparation Method
|
Miniature osmotic infusion pumps which deliver saline-DMSO (50% saline-50% DMSO) solution or phenamil in saline-DMSO were implanted subcutaneously in male Sprague-Dawley rats (age, 6 to 7 weeks; weight, 250 to 300 g) between the scapulae and connected via a catheter advanced into the left carotid artery. Four rats were used for each condition. Phenamil (15 or 30 mg/kg of body weight/day) was administered continuously for 21 days at an infusion rate of 1 ml/h. The rats were subjected to hypobaric hypoxia (10.5% oxygen) or normoxia (room air) for 21 days.
|
|
Dosage form
|
15 or 30 mg/kg, Miniature osmotic infusion pump
|
|
Applications
|
Phenamil reduces chronic-hypoxia-induced pulmonary artery hypertension (PAH).
|
|
参考文献:
[1] : Lo K W H, Ulery B D, Kan H M, et al. Evaluating the feasibility of utilizing the small molecule phenamil as a novel biofactor for bone regenerative engineering[J]. Journal of tissue engineering and regenerative medicine, 2014, 8(9): 728-736.
[2] :Chan M C, Weisman A S, Kang H, et al. The amiloride derivative phenamil attenuates pulmonary vascular remodeling by activating NFAT and the bone morphogenetic protein signaling pathway[J]. Molecular and cellular biology, 2011, 31(3): 517-530.
|
没有评价数据