Phenamil (methanesulfonate)

Phenamil methanesulfonate, an analog of Amiloride (HY-B0285), is a more potent and less reversible epithelial sodium channel (ENaC) blocker with an IC₅₀ of 400 nM^[2]. Phenamil methanesulfonate is also a competive inhibitor of TRPP3 and inhibits TRPP3-mediated Ca²⁺ transport with an IC₅₀ of 140 nM in a Ca²⁺ uptake assay^[1]. Phenamil methanesulfonate is an intriguing small molecule to promote bone repair by strongly activating BMP signaling pathway^[4]. Phenamil methanesulfonate is used for the research of cystic fibrosis lung disease^[5]. In Vitro: TRPP3, a member of the transient receptor potential (TRP) superfamily of cation channels, is a Ca²⁺-activated channel permeable to Ca²⁺, Na⁺, and K⁺. TRPP3 is implicated in regulation of pH-sensitive action potential in spinal cord neurons.
Phenamil methanesulfonate (1 μM) decreases ⁴⁵Ca²⁺ uptake in a radiotracer uptake assay. It inhibits TRPP3-mediated Ca²⁺ transport with an IC₅₀ value of 0.28 μM in oocytes expressing TRPP3 or H2O-injected oocytes^[1].
Phenamil methanesulfonate is a more potent ENaC blocker than Amiloride, it inhibits the epithelial sodium channel (ENaC) with an IC₅₀?of 400 nM (Amiloride=776 nM)^[2].
Phenamil methanesulfonate inhibits basal short-circuit currents with IC₅₀ values of 75 and 116 nM, respectively in both human and ovine bronchial epithelia cells^[3].
Phenamil methanesulfonate (0-20 μM; 14 days) elevates adipogenic gene expression, PPARγ, Fabp4, and lipoprotein lipase expression in a concentration-dependent manner ,and regulates adipogenesis in C3H10T1/2 cells^[4].
Phenamil methanesulfonate (0-20 μM; 7 or 14 days) modulates MC3T3-E1 osteoblastic differentiation, it increases Alkaline phosphatase (ALP) activity in MC3T3-E1 cells in a concentration-dependent manner^[4].
In Vivo: Phenamil methanesulfonate (subcutaneous injection; 15 or 30 mg/kg; 21 days; infusion rate of 1 ml/h) reduces chronic-hypoxia-induced pulmonary artery hypertension (PAH). Additionally, the mRNA level of SMA, SM22, Id3, and Trb3 from the lung sample are also decreased by Phenamil under hypoxia or normoxia in rats. However, phenamil has little effect on pulmonary vasculature under physiological conditions^[5].