title: RS-127445: a selective, high affinity, orally bioavailable 5-HT2B receptor antagonist.
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 (pK(B) = 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 (+/-)alpha-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 is vivo. The therapeutic potential of this molecule is being further evaluated.
authors.affiliation: Department of Molecular Pharmacology, Center for Biological Research, Roche Bioscience, Palo Alto, CA 94304, USA. doug.bonhaus@roche.com
authors.forename: D W
authors.initials: DW
authors.lastname: Bonhaus
authors.forename: L A
authors.initials: LA
authors.lastname: Flippin
authors.forename: R J
authors.initials: RJ
authors.lastname: Greenhouse
authors.forename: S
authors.initials: S
authors.lastname: Jaime
authors.forename: C
authors.initials: C
authors.lastname: Rocha
authors.forename: M
authors.initials: M
authors.lastname: Dawson
authors.forename: K
authors.initials: K
authors.lastname: Van Natta
authors.forename: L K
authors.initials: LK
authors.lastname: Chang
authors.forename: T
authors.initials: T
authors.lastname: Pulido-Rios
authors.forename: A
authors.initials: A
authors.lastname: Webber
authors.forename: E
authors.initials: E
authors.lastname: Leung
authors.forename: R M
authors.initials: RM
authors.lastname: Eglen
authors.forename: G R
authors.initials: GR
authors.lastname: Martin
mesh_terms: D000818:Animals; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D006224:Cricetinae; D006801:Humans; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D011743:Pyrimidines / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D044403:Receptor, Serotonin, 5-HT2B; D011985:Receptors, Serotonin / Q000187:drug effects*; D012702:Serotonin Antagonists / Q000494:pharmacology*; D014664:Vasodilation / Q000187:drug effects
chemical_list: D011743:Pyrimidines; D044403:Receptor, Serotonin, 5-HT2B; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; C121466:2-amino-4-(4-fluoronaphth-1-yl)-6-isopropylpyrimidine; D002118:Calcium