ChemInform Abstract: Design and Synthesis of Piperazinylpyridine Derivatives as Novel 5‐HT_1A Agonists/5‐HT₃ Antagonists for the Treatment of Irritable Bowel Syndrome (IBS).

Abstract

Receptor binding activity X 0280Design and Synthesis of Piperazinylpyridine Derivatives as Novel 5-HT1A Agonists/5-HT 3 Antagonists for the Treatment of Irritable Bowel Syndrome (IBS).-Among this novel synthesized, compounds such as (I) and (II) the derivative (Ib), named TZB-20810, is a promising candidate for further development in the treatment of IBS. The biological results are discussed in detail. -(ASAGARASU*, A.; MATSUI, T.; HAYASHI, H.; TAMAOKI, S.; YAMAUCHI, Y.; SATO, M.; Chem.

Discovery of a Novel 5-HT3 Antagonist/5-HT1A Agonist 3-Amino-5,6,7,8-tetrahydro-2-{4-[4-(quinolin-2-yl)piperazin-1-yl]butyl}quinazolin-4(3H)-one (TZB-30878) as an Orally Bioavailable Agent for Irritable Bowel Syndrome

“…For secondary screening, two in vitro functional tests, a [ 35 S]GTPγS binding assay for 5-HT 1A agonistic activity, and a guinea pig ileum contraction inhibition assay for 5-HT 3 antagonistic activity were carried out for those compounds with high affinities to both receptors (Table 6 and 7). 8,12,13 In the [ 35 S]GTPγS binding assay, E max of compounds 14l and 14r in this series had about 90% and were confirmed to be full 5-HT 1A agonists. In the contraction inhibition assay, these compound showed 90-100% inhibition at 1 μmol/L, confirming that they were 5-HT 3 antagonists.…”

“…In a previous paper, we reported the synthesis of a compound which acts as both a 5-HT 1A agonist and 5-HT 3 antagonist, with the goal being to find a single compound that acts on both receptors as a treatment for IBS. 8 Compounds in this series showed both 5-HT 1A agonist and 5-HT 3 antagonist activity both in vitro and in vivo. From this lead, further structure-activity relationship analysis as well as the design and synthesis of compounds based on our pharmacophore analysis led to the identification of a dual action compound suitable for IBS therapy.…”

“…Aryl piperazines were synthesized from aryl chloride and piperazine by heating at 140 °C in ethylene glycol. 8 These aryl piperazines were treated with 1-bromo-3-chloropropane to give alkyl chloride derivatives (13). The potassium salts (9 and 11) were coupled with 13 Scheme 1.…”

“…Compound affinity for the 5-HT 1A receptor was calculated as percent inhibition of [ 3 H]-1 binding to the 5-HT 1A receptor in a CHO cell membrane sample expressing human 5-HT 1A receptors. 8,12,13 Compound affinity for the 5-HT 3 receptor was calculated as percent inhibition of [ 3 H]BRL-43694 binding in HEK-293 cell membrane sample expressing human 5-HT 3 receptors. Initially, compounds were designed using a pharmacophore model, and after synthesis, compound screening and preliminary structure-activity relationship analysis were used to verify the pharmacophore model.…”

“…In a tertiary screening, compound 14r was studied in two other functional examinations in rats: measurement of 5-HT 1A agonistic activity (lower lip retraction, LLR; flat body posture, FBP; change in rectal temperature, ΔT) and 5-HT 3 antagonistic activity (inhibition of the Bezold-Jarisch (B-J) reflex caused by 5-HT) (Table 9 and 10). 8,12,13 Compound 14r showed disappointing results with respect to 5-HT 1A agonist activity; therefore, we measured the compound total concentrations in the blood and brain (Table 8). 16 The compound total concentration in the brain was found to be too low to have an effect.…”