| Stereochemistry | ABSOLUTE |
| Molecular Formula | C37H45Cl2N2O2 |
| Molecular Weight | 620.671 |
| Optical Activity | UNSPECIFIED |
| Defined Stereocenters | 1 / 1 |
| E/Z Centers | 0 |
| Charge | 1 |
SHOW SMILES / InChI
SMILES
CC(C)OC1=CC(CC(=O)N2CCC[C@@](CC[N+]34CCC(CC3)(CC4)C5=CC=CC=C5)(C2)C6=CC=C(Cl)C(Cl)=C6)=CC=C1
InChI
InChIKey=RPDFDSQFBCJTDY-GAQXSTBRSA-N
InChI=1S/C37H45Cl2N2O2/c1-28(2)43-32-11-6-8-29(24-32)25-35(42)40-19-7-14-37(27-40,31-12-13-33(38)34(39)26-31)18-23-41-20-15-36(16-21-41,17-22-41)30-9-4-3-5-10-30/h3-6,8-13,24,26,28H,7,14-23,25,27H2,1-2H3/q+1/t36?,37-,41?/m1/s1
| Molecular Formula | C37H45Cl2N2O2 |
| Molecular Weight | 620.671 |
| Charge | 1 |
| Count |
MOL RATIO
1 MOL RATIO (average) |
| Stereochemistry | EPIMERIC |
| Additional Stereochemistry | No |
| Defined Stereocenters | 1 / 1 |
| E/Z Centers | 0 |
| Optical Activity | UNSPECIFIED |
Nolpitantium (SR-140333) is a highly selective nonpeptide antagonist of neurokinin-1 (NK1) receptor. Nolpitantium potently, selectively and competitively inhibited substance P binding to NK1 receptors from various animal species, including humans. In vitro, it was a potent antagonist in functional assays for NK1 receptors such as [Sar9, Met(O2)11]substance P-induced endothelium-dependent relaxation of rabbit pulmonary artery and contraction of guinea-pig ileum. Up to 1 mkM, Nolpitantium had no effect in bioassays for NK2 and NK3 receptors. The antagonism exerted by Nolpitantium toward NK1 receptors was apparently non-competitive, with pD2' values between 9.65 and 10.16 in the different assays. Nolpitantium also blocked in vitro [Sar9, Met(O2)11]substance P-induced release of acetylcholine from rat striatum. In vivo, Nolpitantium exerted highly potent antagonism toward [Sar9, Met(O2)11]substance P-induced hypotension in dogs, bronchoconstriction in guinea-pig) and plasma extravasation in rats. Nolpitantium was found to be effective in the modulation of the inflammatory response and airway remodeling in mice. Nolpitantium is reported to cause antagonism of the SP-induced relaxations of human isolated intralobar pulmonary arterial rings. Nolpitantium also blocked the activation of rat thalamic neurons after nociceptive stimulation. Nolpitantium has been shown to reduce the severity of inflammation in trinitrobenzene sulfonic acid-induced colitis in the rat colon. Nolpitantium inhibited mustard oil-induced plasma protein extravasations in the dorsal skin of the rat hind paw. Nolpitantium had been in some phase II clinical trials but further studies were discontinued.
CNS Activity
Originator
Approval Year
Sourcing
PubMed
Sample Use Guides
Single daily doses of 600 mg SR140333B or 1800 mg of SR140333B for eight weeks.
Route of Administration:
Oral
The human breast cancer cell line T47D was used for activity evaluation. Nolpitantium were dissolved in culture medium respectively to obtain experimental concentration (ranging from 10^-9M to 10^-5M). Cell proliferation was assessed using MTT assay. Cells were cultured in 96-well plates and the cell numbers were quantified using a coulter counter (Coulter Electronics, Inc., Hialeah, FL). Each well contained 2x 10^4cells in a total volume of 200 μL. The plate included blank wells (0 cells/mL), control wells (2 x10^4cells/0.2 Ml, untreated group), control wells with DMSO (no cells), control wells treated with SR140333 (Nolpitantium) (10^-9M-10^-5M), control wells treated with SMSP (10^-10M-10^-6M) and control wells treated with SMSP (most effective concentration) combined with different concentrations of SR140333 (10^-9M-10^-5M). Drugs were added on day 3 (at exponential phase) and the assay was performed after 24 hours. For the proliferation assay, 20 μL MTT was added to each well. After 4 hours at 37°C supernatant was removed and 100 μL DMSO was added to each well. The optical density (OD) was detected in the microplate reader at 570 nm wavelength
