| Bioactivity | TRAM-34 is a highly selective blocker of intermediate-conductance calcium-activated K+ channel (IKCa1) (Kd=20 nM). | ||||||||||||
| Target | Kd: 20 nM (IKCa1) | ||||||||||||
| Invitro | TRAM-34 selectively blocks the IKCa1 current (Kd=25 nM), TRAM-34 also blocks IKCa1 currents in human T84 colonic epithelial cells with equivalent potency (Kd=22 nM). TRAM-34 inhibits the cloned and the native IKCa1 channel in human T lymphocytes with a Kd of 20-25 nM and is 200- to 1,500-fold selective over other ion channels. The dose-response curve reveals a Kd of 20±3 nM and a Hill coefficient of 1.2 with 1 μM calcium in the pipette[1]. TRAM-34, a specific inhibitor of KCa 3.1 channels increased or decreased cell proliferation depending on the concentration. At intermediate concentrations (3-10 µM) TRAM-34 increased cell proliferation, whereas at higher concentrations (20-100 µM) TRAM-34 decreased cell proliferation. The enhancement of cell proliferation caused by TRAM-34 is blocked by the oestrogen receptor antagonists ICI182,780 and tamoxifen. TRAM-34 also increases progesterone receptor mRNA expression, decreased oestrogen receptor-α mRNA expression and reduced the binding of radiolabelled oestrogen to MCF-7 oestrogen receptor, in each case mimicking the effects of 17β-oestradiol[2]. | ||||||||||||
| In Vivo | Mice (n=5) injected intravenously with a single dose of TRAM-34 (0.5 mg/kg; 29 μM) appeared clinically normal during the 7-day study. The body-weight data of the TRAM-34-treated group (day 1:17.8 g; day 7: 27.0 g) are similar to control mice injected with the vehicle (day 1: 17.4 g; day 7: 23.4 g). Collectively, data from these limited toxicity studies suggest that TRAM-34 is not acutely toxic at ≈500-1,000 times the channel-blocking dose[1].Treatment with TRAM-34 results in a significant reduction in hematoxylin & eosin (H&E) defined lesion area with the mean infarct size being reduced from 22.6±3.6% in the controls (n=8) to 11.3±2.8% in rats treated with 10 mg/kg TRAM-34 (n=6, mean±s.e.m., P=0.039) and to 8.1±1.9% in rats treated with 40 mg/kg TRAM-34 (n=8; P=0.004). The treatment also tended to reduce brain shrinkage. However, the results are only statistically significant with 40 mg/kg TRAM-34 (P=0.013), but not for the 10 mg/kg group (P=0.11)[3]. | ||||||||||||
| Name | TRAM-34 | ||||||||||||
| CAS | 289905-88-0 | ||||||||||||
| Formula | C22H17ClN2 | ||||||||||||
| Molar Mass | 344.84 | ||||||||||||
| Appearance | Solid | ||||||||||||
| Transport | Room temperature in continental US; may vary elsewhere. | ||||||||||||
| Storage |
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| Reference | [1]. Wulff H, et al. Design of a potent and selective inhibitor of the intermediate-conductance Ca2+-activated K+ channel, IKCa1: a potential immunosuppressant. Proc Natl Acad Sci U S A. 2000 Jul 5;97(14):8151-6. [2]. Roy JW, et al. The intermediate conductance Ca2+-activated K+ channel inhibitor TRAM-34 stimulates proliferation of breast cancer cells via activation of oestrogen receptors. Br J Pharmacol. 2010 Feb 1;159(3):650-8. [3]. Chen YJ, et al. The KCa3.1 blocker TRAM-34 reduces infarction and neurological deficit in a rat model of ischemia/reperfusion stroke. J Cereb Blood Flow Metab. 2011 Dec;31(12):2363-74. |