RS 127445 是一种可口服的，高亲和力选择性5-HT2B受体拮抗剂，pKi为 9.5，比作用于其他受体和离子通道的选择性高 1000 倍。

RS 127445 is a selective, high affinity, orally bioavailable 5-HT2B receptor antagonist(pKi : 9.5).

RS 127445 potently displaced [3H]-5-HT from human recombinant 5-HT2B receptors expressed in CHO-K1 cells.?The affinity (pKi value) of RS-127445 for the 5-HT2B receptor was 9.5±0.1 (n=9).?RS-127445 was selective for the 5-HT2B receptor, having approximately 1000 fold lower affinity for the human?recombinant 5-HT2A, 5-HT2C, 5-HT5, 5-HT6 and 5-HT7 receptors, a 5-HT1A receptor in rat brain membranes, a 5-HT1B/D receptor in bovine caudate, and a monoamine uptake site in rabbit platelets[1]

RS 127445 (5 mg kg^?1) was administered to rats by oral, intraperitoneal and intravenous routes.?Peak plasma concentrations were rapidly achieved with the highest concentrations being found at the first time-point measured following intravenous and intraperitonael administration (0.08 h) and by 0.25 h following dosing by the oral route of administration.?RS-127445 was cleared from plasma with an estimated terminal elimination half-life of approximately 1.7 h. The bioavailability of RS-127445, when administered by the oral and intraperitoneal routes was approximately 14 and 62% of that obtained by intravenous administration .?To test?whether plasma levels were proportional to the dose administered, RS-127445 was given by the intraperitoneal route at doses of 1, 3 and 10 mg kg^?1.?Increasing the dose of RS-127445 resulted in proportional increases in its concentration in the plasma[1]

Rats were euthanized.?Right and left external jugular veins were dissected, cleaned of connective tissues and cut into ring segments approximately 5 mm long.?Tungsten hooks (0.125 mm diameter) were inserted through the lumen of the vein and connected to tension transducers.?Tissues were kept in 10 ml organ baths containing Kreb's solution supplemented with cocaine (30 μm), corticosterone (30 μm), ketanserin (0.3 μm) and indomethacin (3 μm) at 37°C at a resting tension of 0.5 g.?Prior to the initiation of any studies, monamine oxidases were inactivated by a 30 min pre exposure of the tissue to pargyline (0.1 mm).?The veins were then exposed to 0.1 μm U46619 (9,11-dideoxy-9 α, 11 aα-methano-epoxy-PGF2α;?a thromboxane A2 mimetic) until a stable contraction was attained.?Acetylcholine (0.1 μm) was used to verify the integrity of the endothelium and to determine the maximum amount of nitric?oxide-dependent relaxation that was achievable.?After washout of the acetylcholine and recontraction with U46619, cumulative concentration-response curves to (±)-α-methyl-5-HT were constructed.?When maximum relaxation was reached, the baths were rinsed, and the tissues were maintained undisturbed for 2 h. Antagonists (RS 127445)were then added to the bath and allowed to equilibrate with the tissue for at least 1 h before a second concentration-response curve to (±)-α-methyl-5-HT was generated[1].

199864-86-3

C17H17ClFN3

317.79

MT 500;4-(4-氟-1-萘基)-6-(1-甲基乙基)-2-嘧啶胺盐酸盐;RS 127445;RS-127445 hydrochloride

DMSO:31 mg/mL (97.55 mM)
Powder: -20°C for 3 years
In solvent: -80°C for 2 years