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RS‐127445: a selective, high affinity, orally bioavailable 5‐HT 2B receptor antagonist
Author(s) -
Bonhaus Douglas W,
Flippin Lee A,
Greenhouse Robert J,
Jaime Saul,
Rocha Cindy,
Dawson Mark,
Van Natta Kristine,
Chang L K,
PulidoRios Tess,
Webber Andrea,
Leung Edward,
Eglen Richard M,
Martin Graeme R
Publication year - 1999
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0702632
Subject(s) - receptor , pharmacology , receptor antagonist , chemistry , antagonist , 5 ht receptor , in vivo , g protein coupled receptor , medicine , endocrinology , biochemistry , biology , serotonin , microbiology and biotechnology
Efforts to define 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 deficiency, we developed a series of naphthylpyrimidines as potentially useful 5‐HT 2B receptor antagonists. RS‐127445 (2‐amino‐4‐(4‐fluoronaphth‐1‐yl)‐6‐isopropylpyrimidine) was found to have 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. In cells expressing human recombinant 5‐HT 2B receptors, RS‐127445 potently antagonized 5‐HT‐evoked 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 (±)α‐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. 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‐HT 2B receptors for at least 4 h. In conclusion, RS‐127445 is a selective, high affinity 5‐HT 2B 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