RS‐127445: a selective, high affinity, orally bioavailable 5‐HT2B receptor antagonist

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Abstract
Efforts to define precisely the role of 5‐HT2B receptors in normal and disease processes have been hindered by the absence of selective antagonists. To address this deficiency, we developed a series of naphthylpyrimidines as potentially useful 5‐HT2B receptor antagonists. RS‐127445 (2‐amino‐4‐(4‐fluoronaphth‐1‐yl)‐6‐isopropylpyrimidine) was found to have nanomolar affinity for the 5‐HT2B receptor (pKi=9.5±0.1) and 1,000 fold selectivity for this receptor as compared to numerous other receptor and ion channel binding sites. In cells expressing human recombinant 5‐HT2B receptors, RS‐127445 potently antagonized 5‐HT‐evoked formation of inositol phosphates (pKB=9.5±0.1) and 5‐HT‐evoked increases in intracellular calcium (pIC50=10.4±0.1). RS‐127445 also blocked 5‐HT‐evoked contraction of rat isolated stomach fundus (pA2=9.5±1.1) and (±)α‐methyl‐5‐HT‐mediated relaxation of the rat jugular vein (pA2=9.9±0.3). RS‐127445 had no detectable intrinsic activity in these assays. 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−1) produced plasma concentrations predicted to fully saturate accessible 5‐HT2B receptors for at least 4 h. In conclusion, RS‐127445 is a selective, high affinity 5‐HT2B receptor antagonist suitable for use in vivo. The therapeutic potential of this molecule is being further evaluated. British Journal of Pharmacology (1999) 127, 1075–1082; doi:10.1038/sj.bjp.0702632