What question did this study set out to answer?

To identify and characterize a potent, highly selective, and orally bioavailable 5-HT2B receptor antagonist to help elucidate the role of 5-HT2B receptors in physiology and disease.

July 1, 1999British Journal of PharmacologyOpen Access

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

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Authors

DBDouglas W. BonhausRoche (Switzerland)LFLee A. FlippinFibroGen (United States)RGRobert GreenhouseStanford University

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Implication

Preclinical pharmacological evaluation demonstrates potent and selective 5-HT2B receptor antagonism by RS-127445, highlighting its utility for in vivo investigation.

Key Points

To identify and characterize a potent, highly selective, and orally bioavailable 5-HT2B receptor antagonist to help elucidate the role of 5-HT2B receptors in physiology and disease.
Synthesized a series of naphthylpyrimidines and evaluated the binding affinity and selectivity of RS-127445 against 5-HT2B and other receptors or ion channels.
Assayed functional antagonism in cells expressing human recombinant 5-HT2B receptors (measuring inositol phosphate formation and intracellular calcium) and in isolated rat tissues (stomach fundus and jugular vein).
Measured pharmacokinetic properties, including oral and intraperitoneal bioavailability and plasma clearance, in rats.
RS-127445 displayed sub-nanomolar affinity for the 5-HT2B receptor (pKi = 9.5 ± 0.1) with at least 1,000-fold selectivity over other evaluated receptors and ion channels.
The compound potently blocked 5-HT-stimulated inositol phosphates (pKB = 9.5 ± 0.1), calcium mobilization (pIC50 = 10.4 ± 0.1), rat stomach fundus contraction (pA2 = 9.5 ± 1.1), and jugular vein relaxation (pA2 = 9.9 ± 0.3) without intrinsic activity.
In rats, oral and intraperitoneal bioavailabilities were 14% and 60%, respectively, with an intraperitoneal dose of 5 mg/kg maintaining receptor-saturating plasma levels for at least 4 hours.

Cite This Study

Bonhaus et al. (1999) studied this question.

synapsesocial.com/papers/6a12b215c031bb6829a71e56 https://doi.org/10.1038/sj.bjp.0702632

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Implication

Preclinical pharmacological evaluation demonstrates potent and selective 5-HT2B receptor antagonism by RS-127445, highlighting its utility for in vivo investigation.

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

Discussion

Member takes

Implication

Key Points

Cite This Study

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

Discussion

Member takes

Implication

Key Points

Cite This Study

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