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New hypoglycemic effects of indorenate mediated by the 5-HT1a and 5-HT2a receptors: In vivo and in silico studies

Giacoman-Martínez, Abraham123; Almanza Pérez, Julio César2; Alarcón-Aguilar, Francisco Javier2; Rosiles-Alanís, Wendoline4; Villafaña, Santiago3; Romero-Nava, Rodrigo3; Aguayo-Cerón, Karla Aidee3; Huang, Fengyang5; Hong, Enrique1

Published Oct 30, 2025 on Dryad. https://doi.org/10.5061/dryad.2jm63xt36

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Abstract

The treatment of metabolic syndrome (MS), characterized by type 2 diabetes (T2D), obesity, dyslipidemias, and cardiovascular problems, requires an integral treatment. In addition to its central activity, serotonin also has peripheral effects, implying regulation of blood glucose and insulin levels. Indorenate is a serotonin analog with antihypertensive properties and possible activity on the metabolism of carbohydrates. However, its effect on glucose levels has not been explored, which is relevant in searching for the indorenate's potential as an alternative to the treatment of MS. This investigation aimed to study the effects of indorenate on glycemia through in vivo and in silico assays. In normal rats, indorenate was co-administered with two serotonergic antagonists: pelanserin (5-HT2a antagonist) and WAY-100635 (5-HT1a antagonist). Indorenate caused a hypoglycemic effect in normal rats. Pelanserin and WAY-100635 inhibited this effect. In diabetic rats, indorenate increased insulin levels. In addition, indorenate decreased glycemia in an euglycemic clamp test, while pelanserin inhibited this effect. In silico, indorenate exhibited a higher affinity and interactions than serotonin for 5-HT2a and 5-HT1a receptors. The data suggest that the hypoglycemic effect of indorenate requires the participation of the 5-HT2a receptor and partially of the 5-HT1a receptor. Finding drugs with beneficial multimodal effects for blood pressure and glycemic control, such as indorenate, might be relevant for treating MS and its associated pathologies.