Exploring the Mechanism and Implications of RS 23597-190 as a 5-HT4 Receptor Antagonist

The study delves into the pharmacological characteristics of RS 23597-190, a compound that has been evaluated both in vitro and in vivo. The compound demonstrated its ability to competitively inhibit 5-HT4 receptor-mediated responses in rat oesophageal muscularis mucosae with a calculated pA2 value and Schild slope, and showed high affinity for 5-HT4 receptors in binding assays. However, it did not affect the contractile responses induced by 5-HT on guinea-pig ileal 5-HT3 receptors at concentrations up to 10 μM.

RS 23597-190 was found to inhibit the high potency phase of the concentration-response curves to 5-HT in guinea-pig ileal mucosal sheets, confirming the involvement of 5-HT4 receptors. In electrophysiological studies, the compound selectively abolished the slow, high potency depolarizing phase induced by 5-HT in rat isolated vagus nerve, while the rapid, transient depolarization was attributed to 5-HT3 receptors.

At 5-HT3 binding sites, RS 23597-190 showed an apparent affinity, with similar values observed in both NG 108-15 cells and rat cerebral cortex membranes. However, the compound exhibited low apparent affinities for a range of other receptors, including 5-HT1A, 5-HT2, muscarinic M subtypes, and dopamine D1 and D2 receptors.

In vivo, RS 23597-190 was found to antagonize the von Bezold Jarisch reflex in conscious rats and 5-HT-induced tachycardia in anaesthetized micropigs. Notably, arrhythmic effects were transiently observed following the administration of the compound.

In summary, RS 23597-190 is identified as a selective and competitive antagonist with high affinity for 5-HT4 receptors, making it a valuable tool for receptor identification in vitro. In vivo, while the compound is rapidly metabolized in pigs, it can antagonize 5-HT3 mediated responses in rats when administered via infusion, suggesting potential for characterizing 5-HT4 receptor function under specific experimental conditions.