The serotonin 5-HT4 receptor: Part 3: Design and pharmacological evaluation of a new class of antagonists

Review of 5-HT4R Ligands: State of Art and Clinical Applications

“…19) as a 5-HT 4 R antagonist with its ability to inhibit 5-HT-induced guinea pig colon contractions (pIC 50 = 6.8). The indoloaminoguanidine 90 [146], in the same family as tegaserod, was described as a 5-HT 4 R antagonist with a pA 2 value of 8.4 and a 25-fold or greater affinity over other 5-HT receptors. Compound 91 and other derivatives with the same framework were described in a patent in 1993 [147] as having 5-HT 4 R antagonist activity with a pIC 50 >6.…”

5‐HT4 Receptor Ligands: Applications and New Prospects

“…It is worth noting that, from the SAR study reported, the activity of these compounds resides only in the indole derivatives, since the carbazimidamide derivatives with the isosteric indole groups are either inactive or only weakly active. The introduction of a small substituent, such as Me or Et, on the aromatic ring of 19 brought about an interesting drop of the intrinsic activity 92 since the compounds became 5-HT4 receptor antagonists. 20 was a competitive and selective antagonist in the assay of the inhibition of 5-HT-induced contractions of guinea-pig ileum (pA2 = 8.4).…”

“…SDZ HTF 919 or tegaserod, a partial 5-HT4 receptor agonist, showed in healthy subject a clear effect on the total colonic transit time (5 mg twice a day) 174 and a significant improvement in phase III clinical trials in patient with constipation-predominant IBS. 92,175 Prucalopride was shown to be effective in healthy subjects to accelerate the colonic transit without modification of the gastric emptying and the small bowel transit. 176 However in patients with severe constipation, a dose-dependent effect of acceleration of the overall transit time was observed 177 and several double-blind clinical studies demonstrated the significant efficacy of the compound in the mean weekly stool frequency.…”

New Esters of 4-Amino-5-chloro-2-methoxybenzoic Acid as Potent Agonists and Antagonists for 5-HT4 Receptors

“…Moreover, 5-HT 4 receptors have been found in rat, guinea pig, and human brain 12 with high receptor concentrations in the striatum and substantia nigra. Considerable progress has been made in the localization of 5-HT 4 receptors and in the study of their functions with the development of potent antagonists such as SDZ 205-557 ( 1 ), SB 204070 ( 2 ), SB 207710 ( 3 ),15a GR 113808 ( 4 ), and carbazimidamide derivatives,17c in particular which have been used as radiolabeled ligands. 12a,15b,c More recently, SB 207266 ( 5 ), an amidic derivative of a tricyclic indole moiety, was reported as the first potent, selective 5-HT 4 receptor antagonist active orally 18a 1 …”