4-(4-FLUORO-1-NAPHTHALENYL)-6-(1-METHYLETHYL)-2-PYRIMIDINAMINE HYDROCHLORIDE

Description

RS 127445 is an orally bioavailable and potent antagonist of the serotonin (5-HT) receptor subtype 5-HT_2B (K_i = 0.32 nM). It is selective for 5-HT_2B over other 5-HT receptor subtypes (K_i = >3 μM for 5-HT_1A, 5-HT_1B, 5-HT_2A, 5-HT_2C, 5-HT₃, 5-HT₅, and 5-HT₆). RS 127445 reduces contraction of rat isolated stomach fundus (pA₂ = 9.5) and lowers intracellular increases in calcium (IC₅₀ = 0.04 nM) induced by 5-HT . It also blocks (±)-α-methyl-5-HT-induced relaxation of isolated rat jugular veins (pA₂ = 9.95). RS 127445 (1-30 mg/kg) reduces peristaltic frequency and fecal output in mice in a dose-dependent manner. Systemic administration of RS 127445 (0.16 mg/kg) reduces basal, but not cocaine-induced, dopamine outflow in the nucleus accumbens of rats and decreases hyperlocomotion induced by cocaine (Item Nos. ISO60176 | 16186 | 22165) or quinpirole.

Uses

RS-127445 is a 5-HT2B receptor antagonist with modest activity against other 5-HT receptors. Selective 5-HT2B receptor antagonist

Biological Activity

High affinity 5-HT 2B receptor antagonist (pK i = 9.5). Displays 1000-fold selectivity for 5-HT 2B with good bioavailability.

in vitro

RS-127445 is a novel high affinity, selective 5-HT2B receptor antagonist devoid of detectable intrinsic activity. RS-127445 is found to have nM affinity and 1000 fold selectivity for the 5-HT2B receptor. RS-127445 is thus among the highest affinity, most selective 5- HT2B receptor ligands. RS-127445 potently blocks the 5-HT evoked increase in inositol phosphate formation and blocks the 5-HT evoked increases in intracellular calcium concentrations with a potency 1000 times greater than that of yohimbine.

in vivo

RS-127445 is readily absorbed with no obvious dose or route-dependent limitations and rapidly absorbed following both oral and intraperitoneal administration with peak plasma concentrations being achieved within 15 min of dosing. RS-127445 concentration in the plasma are achieved are proportional to the administered dose. RS-127445 administrated at dose of 5 mg/kg with approximately 60% of an intraperitoneal dose and 14% of the oral dose is bioavailable. RS-127445 concentration in the plasma is predicted to fully saturate accessible 5-HT2B receptors can be readily achieved and maintained in the rat. RS-127445 administered at 1 to 10 mg/kg with oral significantly inhibits visceral hypersensitivity up to 35 to 74% provoked by restraint stress. Oral RS-127445 produces a significant suppression of TNBS-induced visceral hypersensitivity (15 to 62% inhibition at 3 to 30 mg/ kg), although RS-127445 has no significant effect on the visceral nociceptive threshold of native rats. RS-127445 administrated orally with 1 to 30 mg/kg also dose -dependently reduce the restraint stress-induced defecation in native and TNBS-treated rats. . RS-127445 inhibits colonic motility and defecation.

target

5-HT2B receptor

References

[1] bonhaus d w, flippin l a, greenhouse r j, et al. rs‐127445: a selective, high affinity, orally bioavailable 5‐ht2b receptor antagonist[j]. british journal of pharmacology, 1999, 127(5): 1075-1082.