Exploring the Therapeutic Potential of RS 39604: A Selective and Long-Lasting 5-HT4 Receptor Antagonist

A new drug, RS 39604, has been identified as a selective 5-HT4 receptor antagonist, and its effects are being compared to those of SB 204070. In experiments with guinea pig tissues, both drugs showed inhibitory effects on specific binding, with RS 39604 having a slightly lower potency. RS 39604 demonstrated low affinity for a range of other receptors, but moderate affinity for σ1 and σ2 sites.

In rat esophagus studies, RS 39604 acted as a competitive antagonist to 5-HT-induced effects, while SB 204070 was previously found to be an unsurmountable antagonist. In guinea pig ileal mucosa, RS 39604 also showed antagonistic properties.

In micropigs, RS 39604, when administered intravenously or intraduodenally, led to a dose-dependent decrease in 5-HT-induced tachycardia, with effects lasting over six hours. SB 204070 was comparably potent intravenously but showed no activity intraduodenally.

In conscious mice, RS 39604, given intraperitoneally or orally, resulted in a dose-dependent reduction of 5-HTP-induced diarrhea, whereas SB 204070 was inactive orally. In guinea pigs, RS 39604 antagonized the contractile effects of 5-HT in the colon, while SB 204070 did not show this effect.

Finally, RS 39604 did not impact visceral pain responses in rats, suggesting 5-HT4 receptors are not involved in this type of pain. The overall findings indicate that RS 39604 is a potent and selective 5-HT4 antagonist with oral bioavailability and long-lasting effects, making it a promising candidate for further investigation into the role of 5-HT4 receptors in various physiological and pathological conditions.