1-Oxo-5-hydroxytryptamine:  A Surprisingly Potent Agonist of the 5-HT₃ (Serotonin) Receptor

Abstract

A novel synthetic route to 1-oxo-5-hydroxytryptamine, the benzofuran analogue of serotonin, has been developed. The new synthesis proceeds via the [3+2] cycloaddition of p-benzoquinone and 2,3-dihydrofuran, followed by a Lewis acid-catalyzed isomerization. This molecule proves to be a competent agonist (equipotent to serotonin) of the 5-HT3 receptor, demonstrating that the indolic proton of serotonin is not essential to its activation of the receptor.

A Hydrogen Bond in Loop A Is Critical for the Binding and Function of the 5-HT3 Receptor

“…In our study, m CPBG blocked 100 µM 5-HT-induced currents with an IC 50 of 0.63 µM [pIC 50 = 6.20 ± 0.04 M; n = 5 (Figure )]. Furthermore, 5-FT, another partial agonist of 5-HT 3 receptors , also became an antagonist, blocking 100 µM 5-HT-induced currents with an IC 50 of 13 µM [pIC 50 = 5.26 ± 0.06; n = 3 (Figure )]. Like m CPBG, this compound failed to activate E129Q mutant receptors on its own.…”

Functional Probes of Drug–Receptor Interactions Implicated by Structural Studies: Cys-Loop Receptors Provide a Fertile Testing Ground

“…49 Surprisingly, 1-oxo-5-hydroxytryptamine, in which an O replaces the indole NH of serotonin, is equipotent to serotonin and a full agonist, suggesting that this NH group is not essential to receptor activation. 63 In contrast, serotonin analogues that replace the 5-hydroxy group, such as 5-fluorotryptamine, have notably reduced affinities and low efficacies. 64 Conventional and unnatural amino acid mutagenesis studies suggest that the hydrogen bonding partner for the 5-hydroxy group is E129 on loop A.…”

“…Interestingly, the quaternary trimethylammonium analogue of serotonin (5-HTQ) is as potent as serotonin at this receptor and also forms a strong cation−π interaction with TrpB . Surprisingly, 1-oxo-5-hydroxytryptamine, in which an O replaces the indole NH of serotonin, is equipotent to serotonin and a full agonist, suggesting that this NH group is not essential to receptor activation . In contrast, serotonin analogues that replace the 5-hydroxy group, such as 5-fluorotryptamine, have notably reduced affinities and low efficacies .…”

Oxidative Coupling of Hydroquinone Derivatives with Olefins to Dihydrobenzofurans

“…2,3-Dihydrobenzofurans (DHBs) are important skeletons for bioactive compounds and natural products, and various synthetic approaches have been developed. [1][2][3][4] Among them, benzoquinones (BQs) have been widely utilized as substrates in [3 + 2] cycloaddition with olefins (e.g., styrenes, [5][6][7][8] enol ethers, [9][10][11] allyl silane 12) ) to afford versatile DHBs (Chart 1A). BQs are prepared by the oxidation of hydroquinones (HQs), which can be easily modified by Friedel-Crafts type reactions to the corresponding C2-functionalized hydroquinone (such as compounds bearing an electron-withdrawing group (EWG) at the C2 position, 1, Chart 1C).…”