289905-88-0
289905-88-0 structure
- Name: TRAM-34
- Chemical Name: 1-[(2-chlorophenyl)-diphenylmethyl]pyrazole
- CAS Number: 289905-88-0
- Molecular Formula: C22H17ClN2
- Molecular Weight: 344.837
- Catalog: Biochemical Inhibitor Transmembrane Transporters Potassium Channel Inhibitor
- Create Date: 2018-12-09 11:50:56
- Modify Date: 2024-01-08 08:53:21
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TRAM-34 is a highly selective blocker of intermediate-conductance calcium-activated K+ channel (IKCa1) (Kd=20 nM).
| Name | 1-[(2-chlorophenyl)-diphenylmethyl]pyrazole |
|---|---|
| Synonyms |
TRAM-34
1H-Pyrazole, 1-[(2-chlorophenyl)diphenylmethyl]- 1-[(2-Chlorophenyl)(diphenyl)methyl]-1H-pyrazole 1-[(2-Chlorophenyl)diphenylmethyl]-1H-pyrazole 1-((2-chlorophenyl)diphenylmethyl)-1H-pyrazole Clotrimazole Impurity 8 |
| Description | TRAM-34 is a highly selective blocker of intermediate-conductance calcium-activated K+ channel (IKCa1) (Kd=20 nM). |
|---|---|
| Related Catalog | |
| Target |
Kd: 20 nM (IKCa1)[1] |
| In Vitro | 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]. |
| Kinase Assay | MCF-7 cell protein (250 µg) is incubated at room temperature for 2 h in TEDG buffer in the presence of 0.1 nM [2,4,6,7,16,17-3H(N)]-oestradiol ([3H]-E2) (110 Ci/mmol) in a total final volume of 500 µL. Non-specific binding is assessed in the presence of a 100-fold excess of non-radioactive E2. TRAM-34 and E2 standards are diluted in phenol red-free 5% DCC-FBS MEM containing supplements before being added to the cytosolic protein. A vehicle control comprised of 5% DCC-FBS MEM containing supplements with 0.7% DMSO. To separate ER-bound [3H]-E2 from unbound [3H]-E2, 250 µL of hydroxylapatite (HAP, 60% in TEDG buffer) is added, the mixture is vortexed every 5 min over 15 min and centrifuged at 1000×g for 10 min. The HAP-[3H]-E2-ER complex is washed with TEDG buffer, centrifuged and the wash step repeated. To elute [3H]-E2 from the HAP-[3H]-E2-ER complex, 500 µL of 100% ethanol is added and the mixture then incubated for 15 min and centrifuged at 1034×g for 10 min. The separated [3H]-E2 is removed and added to 2 mL of scintillation fluid. Radioactivity is quantified using a Beckman LS 5000TA scintillation counter. Competition of [3H]-E2 with TRAM-34 is assayed in quadruplicate on four independent protein extractions. An apparent dissociation constant of 0.135±0.034 nM (n=3) and a maximum binding capacity of 48.3±5.4 fmol/mg (n=3) are determined by Scatchard analysis[2]. |
| Animal Admin | Mice[1] Five CF-1BR mice (17-19 g) are injected intravenously with a single 1.0-ml dose of 0.5 mg/kg TRAM-34 (in mammalian Ringer solution with 1% ethanol and 2.5% BSA). Five control mice are injected with an equal volume of the vehicle. Mice are observed for adverse effects immediately after dosing, at 4 h after injection and daily for 7 days. Rats[3] Adult male Wistar rats weighing 160 to 180 g are used. Rats receive TRAM-34 at 10 mg/kg, 40 mg/kg or vehicle (Miglyol 812 neutral oil at 1 μL/g) twice daily intraperitoneally for 7 days starting 12 hours after reperfusion. Neurological deficits are scored according to a 4-score test and a tactile and proprioceptive limb-placing test as follows: (1) 4-score test (higher score for more severe neurological deficits): 0=no apparent deficit; 1=contralateral forelimb is consistently flexed during suspension by holding the tail; 2=decreasing grip ability on the contralateral forelimb while tail pulled; 3=spontaneous movement in all directions but circling to contralateral side when pulled by the tail; 4=spontaneous contralateral circling or depressed level of consciousness. (2) 14-score limb-placing test (lower score for more severe neurological deficits): proprioception, forward extension, lateral abduction, and adduction are tested with vision or tactile stimuli. For visual limb placing, rats are held and slowly moved forward or lateral toward the top of a table. Normal rats placed both forepaws on the tabletop. Tactile forward and lateral limb placing are tested by lightly contacting the table edge with the dorsal or lateral surface of a rat's paw while avoiding whisker contact and covering the eyes to avoid vision. |
| References |
| Density | 1.1±0.1 g/cm3 |
|---|---|
| Boiling Point | 510.2±50.0 °C at 760 mmHg |
| Melting Point | 145-147ºC |
| Molecular Formula | C22H17ClN2 |
| Molecular Weight | 344.837 |
| Flash Point | 262.4±30.1 °C |
| Exact Mass | 344.108032 |
| PSA | 17.82000 |
| LogP | 5.65 |
| Appearance | solid | off-white |
| Vapour Pressure | 0.0±1.3 mmHg at 25°C |
| Index of Refraction | 1.617 |
| Storage condition | 2-8°C |
| Water Solubility | DMSO: ~11 mg/mL | Soluble in DMSO at 2mg/ml. Insoluble in water |
| Symbol |
GHS07 |
|---|---|
| Signal Word | Warning |
| Hazard Statements | H302-H413 |
| Personal Protective Equipment | dust mask type N95 (US);Eyeshields;Gloves |
| Hazard Codes | Xn |
| Risk Phrases | 22 |
| RIDADR | NONH for all modes of transport |
| WGK Germany | 3 |
| HS Code | 2933199090 |
| HS Code | 2933199090 |
|---|---|
| Summary | 2933199090. other compounds containing an unfused pyrazole ring (whether or not hydrogenated) in the structure. VAT:17.0%. Tax rebate rate:13.0%. . MFN tariff:6.5%. General tariff:20.0% |