RS-127445

RS-127445 is a selective, high affinity, orally bioavailable 5-HT_2B receptor antagonist with a pK_i of 9.5. RS-127445 shows 1000 fold selectivity for this receptor as compared to numerous other receptor and ion channel binding sites^[1]. In Vitro: RS-127445 is found to has nanomolar affinity for the 5-HT_2B receptor (pK_i=9.5±0.1) and 1,000 fold selectivity for this receptor as compared to numerous other receptor and ion channel binding sites. RS-127445 potently displaces [³H]-5-HT from human recombinant 5-HT_2B receptors expressed in CHO-K1 cells. The affinity (pK_i value) of RS-127445 for the 5-HT_2B receptor is 9.5±0.1 (n=9). RS-127445 is selective for the 5-HT_2B receptor, having approximately 1000 fold lower affinity for the human recombinant 5-HT_2A, 5-HT_2C, 5-HT₅, 5-HT₆ and 5-HT₇ receptors, a 5-HT_1A receptor in rat brain membranes, a 5-HT_1B/D receptor in bovine caudate, and a monoamine uptake site in rabbit platelets. RS-127445 potently blocks the 5-HT (10 nM) evoked increases in intracellular calcium concentrations in the HEK-293 cells expressing the 5-HT_2B receptor (pIC₅₀ of 10.4±0.1). In cells expressing human recombinant 5-HT_2B receptors, RS-127445 potently antagonizes 5-HT-evoked formation of inositol phosphates (pK_B=9.5±0.1) and 5-HT-evoked increases in intracellular calcium (pIC₁₀=10.4±0.1). RS-127445 also blocks 5-HT-evoked contraction of rat isolated stomach fundus (pA_2B=9.5±1.1) and (±)α-methyl-5-HT-mediated relaxation of the rat jugular vein (pA₂=9.9±0.3)^[1]. In Vivo: In rats, the fraction of RS-127445 that is bioavailable via the oral or intraperitoneal routes is 14 and 60% respectively. Intraperitoneal administration of RS-127445 (5 mg/kg) produced plasma concentrations predicted to fully saturate accessible 5-HT_2B receptors for at least 4 h.RS-127445 (5 mg/kg) is administered to rats by oral, intraperitoneal and intravenous routes. Peak plasma concentrations are 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 is 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 is approximately 14 and 62% of that obtained by intravenous administration. Approximately 60% of an intraperitoneal dose and 14% of the oral dose of RS-127445 (5 mg/kg) is bioavailable^[1]. RS-127445 (1-30 mg/kg), dose-dependently reduces faecal output, reaching significance at 10 and 30 mg/kg (n=6-11). In blood and brain, >98% of RS-127445 is protein-bound^[2].