RS‐127445: a selective, high affinity, orally bioavailable 5‐HT_2B receptor antagonist

Abstract

to de®ne precisely the role of 5-HT 2B receptors in normal and disease processes have been hindered by the absence of selective antagonists. To address this de®ciency, we developed a series of naphthylpyrimidines as potentially useful 5-HT 2B receptor antagonists. 2 RS-127445 (2-amino-4-(4-¯uoronaphth-1-yl)-6-isopropylpyrimidine) was found to have nanomolar a nity 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. 3 In cells expressing human recombinant 5-HT 2B receptors, RS-127445 potently antagonized 5-HTevoked formation of inositol phosphates (pK B =9.5+0.1) and 5-HT-evoked increases in intracellular calcium (pIC 50 =10.4+0.1). RS-127445 also blocked 5-HT-evoked contraction of rat isolated stomach fundus (pA 2 =9.5+1.1) and (+)a-methyl-5-HT-mediated relaxation of the rat jugular vein (pA 2 =9.9+0.3). RS-127445 had no detectable intrinsic activity in these assays. 4 In rats, the fraction of RS-127445 that was bioavailable via the oral or intraperitoneal routes was 14 and 60% respectively. Intraperitoneal administration of RS-127445 (5 mg kg 71 ) produced plasma concentrations predicted to fully saturate accessible 5-HT 2B receptors for at least 4 h. 5 In conclusion, RS-127445 is a selective, high a nity 5-HT 2B receptor antagonist suitable for use in vivo. The therapeutic potential of this molecule is being further evaluated.

Serotonin 5-HT2BReceptors Are Required for 3,4-Methylenedioxymethamphetamine-Induced Hyperlocomotion and 5-HT ReleaseIn VivoandIn Vitro

“…RS-127445 was found to have subnanomolar affinity for the 5-HT 2B receptor (pK i ϭ 9.5 Ϯ 0.1) and at least 1000-fold selectivity for this receptor compared with numerous other receptors and monoamine uptake sites (Bonhaus et al, 1999). Some of these receptors are of special interest in MDMA-induced locomotion, especially 5-HT 2A , 5-HT 2C , and 5-HT 1B receptors, but also 5-HT and DA transporters (Bankson and Cunningham, 2001).…”

“…MDMA (Sigma-Aldrich, Saint-Quentin Fallavier, France) was dissolved in 0.9% (w/v) NaCl solution (saline); RS127445 (Bonhaus et al, 1999) was kindly provided by Roche Bioscience (Indianapolis, IN) and slowly dissolved in saline solution. BW723C86 (Sigma-Aldrich) was dissolved in saline solution.…”

“…To evaluate the role of 5-HT 2B receptors in mediating the actions of MDMA, we used two parallel approaches: a pharmacological approach using the most selective 5-HT 2B receptor antagonist currently known, 2-amino-4-(4-fluoronaphth-1-yl)-6-isopropylpyrimidine (RS127445) (Bonhaus et al, 1999), and a genetic approach using mice lacking the 5-HT 2B receptor . Our results demonstrate that functional 5-HT 2B receptors are required for MDMA-induced behavioral effects and 5-HT release in vivo and in vitro.…”

The effects of benzofury (5-APB) on the dopamine transporter and 5-HT2-dependent vasoconstriction in the rat

“…A simple and sensitive in vitro assay for acute effects at the 5-HT 2B receptor is the rat gastric fundus contraction assay, first described by (Sir) John Vane. Here we found 5-APB to cause contraction of the rat fundus, an effect antagonised by the specific 5-HT 2B receptor antagonist RS127445 (Bonhaus et al, 1999). We also found 5-HT and MDMA to cause contraction of the fundus, with 5-APB having a greater efficacy than MDMA, a drug already linked to valvulopathies (Bhattacharyya et al, 2009).…”

“…In comparison to 5-HT, 5-APB and MDMA appeared to be partial agonists as the maximal responses to these drugs were lower than 5-HT itself. The concentration-effect curves for all three agonists were significantly right-shifted by the 5-HT 2B antagonist RS 127445 (1 µM; Bonhaus et al, 1999); the results for 5-APB are shown in figure 4C.…”