GSK961081, also known as Batefenterol and TD-5959, is a Muscarinic Antagonist and β2-Agonist possessing both muscarinic antagonist (MA) and β2-adrenoceptor agonist (BA) properties (MABA). Batefenterol is a novel first-in-class inhaled bifunctional compound possessing both muscarinic antagonist (MA) and β2-adrenoceptor agonist (BA) properties (MABA). GSK-961081 displayed high affinity for hM2 (Ki = 1.4 nM), hM3 muscarinic receptors (Ki = 1.3 nM) and hβ2-adrenoceptors (Ki = 3.7 nM). GSK-961081 behaved as a potent hβ2-adrenoceptor agonist (EC50 = 0.29 nM for stimulation of cAMP levels) with 440- and 320-fold functional selectivity over hβ1- and hβ3-adrenoceptors, respectively.
 |
Source | J Pharmacol Exp Ther (2014). Figure 2. GSK-961081 |
| Method | Activity at Human b-Adrenoceptor Subtypes | |
| Cell Lines | BEAS-2B cells | |
| Concentrations | 10, 30, and 100 nM | |
| Incubation Time | 20 minutes | |
| Results | As shown in Table 3 and Fig. 2, GSK-961081 had an IA of 0.8, significantly greater than that of salmeterol (0.35) and albuterol (0.40), but lower than that of formoterol (0.95). |
| Cell Experiment | |
|---|---|
| Cell lines | HEK or CHO-K1 cells |
| Preparation method | Cells were incubated with increasing concentrations of GSK-961081 for 20 minutes at 37°C. The cells were stimulated with an EC90 concentration of the muscarinic agonist oxotremorine. The EC90 concentration was determined by generating an agonist concentration-response curve with the same batch of cells before the experiment. |
| Concentrations | 10, 30, and 100 nM |
| Incubation time | 20 minutes |
| Animal Experiment | |
|---|---|
| Animal models | |
| Formulation | |
| Dosages | |
| Administration | |
| Molecular Weight | 740.25 |
| Formula | C40H42ClN5O7 |
| CAS Number | 743461-65-6 |
| Solubility (25°C) | DMSO 90 mg/mL |
| Storage |
Powder -20°C 3 years ; 4°C 2 years In solvent -80°C 6 months ; -20°C 1 month |
| Species | Mouse | Rat | Rabbit | Guinea pig | Hamster | Dog |
| Weight (kg) | 0.02 | 0.15 | 1.8 | 0.4 | 0.08 | 10 |
| Body Surface Area (m2) | 0.007 | 0.025 | 0.15 | 0.05 | 0.02 | 0.5 |
| Km factor | 3 | 6 | 12 | 8 | 5 | 20 |
| Animal A (mg/kg) = Animal B (mg/kg) multiplied by | Animal B Km |
| Animal A Km |
For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.
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