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Selective and functional 5-hydroxytryptamine4 receptor antagonism by SB 207266
K A Wardle1, S Bingham, E S Ellis
1SmithKline Beecham Pharmaceuticals, New Frontiers Science Park, Harlow, Essex.
British Journal of Pharmacology
|June 1, 1996
Summary
SB 207266 is a potent and selective 5-HT4 receptor antagonist, demonstrating efficacy in both in vitro and in vivo models. This novel orally active amide offers a valuable tool for studying 5-HT4 receptor function.
Area of Science:
- Pharmacology
- Gastroenterology
- Neuroscience
Background:
- The 5-HT4 receptor plays a role in gastrointestinal motility and other physiological processes.
- Selective antagonists are crucial for understanding receptor function and developing therapeutics.
Purpose of the Study:
- To characterize the pharmacological profile of SB 207266, a novel 5-HT4 receptor antagonist.
- To evaluate its potency, selectivity, and activity in vitro and in vivo.
Main Methods:
- In vitro studies using guinea-pig distal colon longitudinal muscle myenteric plexus (LMMP) to assess 5-HT-evoked contractions.
- In vivo studies in the dog Heidenhain pouch model to evaluate antagonism of 5-HT-evoked contractions after oral and intravenous administration.
Main Results:
- SB 207266 demonstrated high potency (apparent pA2 10.6 +/- 0.1) and selectivity as a 5-HT4 receptor antagonist in guinea-pig colon.
- In dogs, SB 207266 dose-dependently antagonized 5-HT-evoked contractions with ID50 values of 1.3 µg/kg (i.v.) and 9.6 µg/kg (oral).
- Antagonistic effects were reversible and long-lasting, particularly after oral administration.
Conclusions:
- SB 207266 is a highly potent, selective, and orally active 5-HT4 receptor antagonist.
- It represents the first orally active amide antagonist in this class.
- SB 207266 is a significant new tool for in vitro and in vivo research on 5-HT4 receptor function.