TPC2-A1-P

• CAT Number: I045452
• CAS Number: 2804595-86-4
• Molecular Formula: C20H21BrF3NO3
• Molecular Weight: 460.28
• Purity: ≥95%
• Synonyms: 5-[5-bromo-2-(trifluoromethoxy)phenyl]-1-(cyclohexylmethyl)-2-methylpyrrole-3-carboxylic acid
• InChI: InChI=1S/C20H21BrF3NO3/c1-12-15(19(26)27)10-17(25(12)11-13-5-3-2-4-6-13)16-9-14(21)7-8-18(16)28-20(22,23)24/h7-10,13H,2-6,11H2,1H3,(H,26,27)
• InChIKey: INDFMVADKKBSSU-UHFFFAOYSA-N
• SMILES: CC1=C(C=C(N1CC2CCCCC2)C3=C(C=CC(=C3)Br)OC(F)(F)F)C(=O)O

TPC2-A1-P is a powerful and membrane permeable agonist of two pore channel 2 (TPC2) with an EC50 of 10.5 μM. TPC2-A1-P plays its role by mimicking the physiological actions of PI(3,5)P2. TPC2-A1-P also shows higher potency to induce Na2+ mobilisation from TPC2 than TPC-A1-N (HY-131614). TPC2-A1-P can be used to probe different functions of TPC2 channels in intact cells[1][2][3].
Two-pore channels (TPC1-3) are ancient members of the voltage-gated ion channel superfamily. TPCs are expressed throughout the endo-lysosomal system and regulates the trafficking of various cargoes[1].TPC2 can mediate different physiological and possibly pathophysiological effects depending on how it is activated.?The?ion selectivity of TPC2 is not fixed but rather agonist-dependent. TPC2 is a unique example of an ion channel that conducts different ions in response to different activating ligands[1].TPC2-A1-P (10 μM) reproducibly evokes Ca2+?signals, and TPC2-A1-P response reachs its plateau slower than TPC2-A1-N (HY-131614). The EC50?in full concentration-effect relationships for the plateau response is 10.5 μM for TPC2-A1-P in a cell line stably expressing TPC2L11A/L12A.TPC2-A1-P (10-30 μM) induces Ca2+?signals in Hela cells expressing TPC2 in the presence but not absence of extracellular Ca2+. However, the responses are smaller and delayed compared to TPC2-A1-N (HY-131614), consistent with the results obtained in cells stably expressing TPC2L11A/L12A. TPC2-A1-P fails to induce Ca2+?signals in cells expressing ‘pore-dead’ TPC2L11A/L12A/L265P and also fails to evoke Ca2+?signals in cells expressing human TRPML1 re-routed to the plasma membrane (TRPML1ΔNC)[1].In endo-lysosomal patch-clamp experiments, TPC2-A1-P (10 μM) evokes currents in endo-lysosomes isolated from cells expressing TPC2 and TPC2M484L, the currents evoked by TPC2-A1-P are significantly larger than those evoked by TPC2-A1-N (HY-131614) in both wild-type and gain-of-function variant,and exhibits an EC50?value of 0.6 μM for TPC2-A1-P[1].

Reference

[1]. Susanne Gerndt, et al. Agonist-mediated switching of ion selectivity in TPC2 differentially promotes lysosomal function. Elife. 2020 Mar 16;9:e54712.
 [Content Brief]

[2]. Gerndt S, et al. Discovery of lipophilic two-pore channel agonists. FEBS J. 2020;287(24):5284-5293.
 [Content Brief]

[3]. Xuhui Jin, et al. Targeting Two-Pore Channels: Current Progress and Future Challenges. Trends Pharmacol Sci. 2020 Aug;41(8):582-594.
 [Content Brief]