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

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‐flu...

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Published in:British journal of pharmacology 1999-07, Vol.127 (5), p.1075-1082
Main Authors: Bonhaus, Douglas W, Flippin, Lee A, Greenhouse, Robert J, Jaime, Saul, Rocha, Cindy, Dawson, Mark, Van Natta, Kristine, Chang, L K, Pulido‐Rios, Tess, Webber, Andrea, Leung, Edward, Eglen, Richard M, Martin, Graeme R
Format: Article
Language:English
Subjects:
5‐HT
5‐HT2B receptor
Animals
Biological and medical sciences
Calcium - metabolism
Cell receptors
Cell structures and functions
CHO Cells
Cricetinae
Fundamental and applied biological sciences. Psychology
Humans
Male
Medical sciences
Molecular and cellular biology
Monoamines receptors (catecholamine, serotonine, histamine, acetylcholine)
Muscle Contraction - drug effects
Neuropharmacology
Neurotransmitters. Neurotransmission. Receptors
Pharmacology. Drug treatments
Pyrimidines - pharmacology
Radioligand Assay
Rats
Rats, Sprague-Dawley
Receptor, Serotonin, 5-HT2B
Receptors, Serotonin - drug effects
RS‐127445
serotonin
Serotonin Antagonists - pharmacology
Serotoninergic system
Vasodilation - drug effects
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Summary: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
ISSN:0007-1188
1476-5381
DOI:10.1038/sj.bjp.0702632